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.     

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.     

Modulation of Type I immediate and Type IV delayed immunoreactivity using direct suggestion and guided imagery during hypnosis

Cutaneous reactivity against histamine skin prick test (Type I) and purified tuberculin protein derivative (Mantoux reaction, Type IV) was studied in eight volunteers under hypnosis. Types I and IV immunoreactivity were modulated by direct suggestion (Type I) and guided imagery (Type IV). The volunteers were highly susceptible subjects, selected by means of the Harvard Group Scale of Hypnotic Susceptibility, Form A. When the volunteers underwent hypnotic suggestion to decrease the cutaneous reaction to histamine prick test, a significant (P less than 0.02) reduction of the flare reaction (area of erythema) was observed compared with control histamine skin prick tests. The wheal reaction did not respond to hypnotic suggestion. Neither wheal nor flare reaction could be increased in size by hypnotic suggestion compared with control histamine skin prick tests. A hypnotic suggestion of increasing the Type IV reaction on one arm and decreasing the reaction on the other revealed a significant difference in both erythema size (P less than 0.02) and palpable induration (P less than 0.01). In two cases the reactions were monitored by laser doppler blood flowmetry and skin thickness measurement by ultrasound. The difference between the suggested increased and decreased reaction was 19% for the laser doppler bloodflow (in favor of the augmented side), and 44% for the dermal infiltrate thickness. This study objectively supports the numerous uncontrolled case reports of modulation of immunoreactivity in allergic diseases involving both Type I and Type IV skin reactions following hypnotic suggestions.     

The effect of ranitidine, alone and in combination with clemastine, on allergen-induced cutaneous wheal-and-flare reactions in human skin

The effect of intradermal ranitidine (administered alone and in combination with clemastine) on allergen-mediated wheal-and-flare reactions has been evaluated in a double-blind study on 10 healthy atopic volunteers. Ranitidine alone, administered in doses over a 10(4)-fold concentration range, had no effect on the size either of allergen-induced wheal or flare reactions. Clemastine alone evoked a dose-related inhibition of both wheal and flare. Compared to the inhibition achieved by clemastine alone, the combination of ranitidine with clemastine produced a small but significant increase in inhibition of allergen-induced flare at ranitidine concentrations of 10(-5) mol/L (p less than 0.001) and 10(-6) mol/L (p less than 0.01), and of allergen-induced wheal at ranitidine concentration 10(-5) mol/L (p less than 0.01). Our results provide further evidence for the presence of cutaneous histamine H2 receptors and their participation in the formation of allergen-mediated skin reactions but indicate that the contribution of cutaneous histamine H2-receptor stimulation to the production of immediate wheal-and-flare reactions evoked by allergen is only modest.     

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.     

Herbal supplements and skin testing: the lack of effect of commonly used herbal supplements on histamine skin prick testing

BACKGROUND: The use of herbal supplements is common, yet little is known about their pharmacologic properties. The purpose of this study was to assess the effects of 23 commonly used herbal supplements on histamine skin prick testing (SPT). METHODS: Fifteen healthy volunteers participated in a double-blind, placebo-controlled, single-dose, crossover study. Wheal and flare responses to SPT with histamine phosphate (1 mg/ml) were measured before and 4 h after administration of each of the 23 popular herbal supplements, fexofenadine (60 mg) and placebo. Wheal and flare areas were recorded with tracings performed 10 min after the prick test and measured with a PC-digitizer using stereometric software. RESULTS: Fexofenadine significantly suppressed the wheal (P < 0.001) and flare (P = 0.02) areas compared with placebo. None of the herbal supplements caused significant suppression of the wheal and flare areas compared with placebo (P > 0.10). CONCLUSION: When taken in single-doses, the popular herbal supplements tested did not significantly affect the histamine skin response. Therefore, it seems unnecessary for clinicians to ask patients to discontinue these herbal supplements prior to allergy skin testing.     

Wheal-and-flare reactions induced by allergen and histamine: evaluation of blood flow with laser Doppler flowmetry

Dermal blood flow was evaluated after skin prick test with histamine and allergen in six patients with seasonal allergic rhinitis. Blood flow was registered continuously for 60 minutes after the test procedure with laser doppler flowmetry, which allows noninvasive measurements. Blood flow was measured close to the skin test in the wheal obtained, and at a greater distance from the prick in the flare reaction. Tests were performed with preloaded skin test needles with histamine and the appropriate allergen freeze-dried on the point of the lancet, as well as with the appropriate negative control. The prick test procedure, by itself, induced a transient increase in blood flow that was normalized again after 9 minutes for the closest measurement. Histamine induced a rapid increase in blood flow in both the flare and wheal reaction that was normalized after about 45 minutes. The increase was significantly higher in the flare compared to the wheal for the time points from 6 1/2 to 13 minutes. Allergen induced a similar increase in blood flow. However, the increase was not noticeable until 2 1/2 minutes after the allergen application and was not completely abolished within 60 minutes. Furthermore, the difference between the flare and wheal reaction, with the higher values for the flare reaction, was present for a longer period of time than for the equivalent histamine measurements. In conclusion, laser doppler flowmetry appears useful for continuous evaluation of vascular changes induced at skin prick tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of beta adrenergic stimulation and blockade on cutaneous reactivity to histamine.

It has been previously demonstrated that iontophoresis of beta adrenergic agents will alter the size of immediate hypersensitivity skin tests. It was unclear whether this alteration was due to an effect on the dermal mast cell (inhibition of histamine release) or on the cutaneous vasculature (inhibition of capillary permeability). For this reason isoproterenol, propranolol, diphenhydramine as a positive control, and saline as a negative control were iontophoresed onto the forearm of 10 atopic and 10 nonatopic adult subjects. In order to bypass histamine release from mast cells the patients were then challenged directly with histamine by the "prick" technique. The size of the resultant wheals was noted. The data obtained allowed the following conclusions: (1) The atopic group responded to histamine with greater wheal size than the nonatopic group. (2) Iontophoresis of diphyenhydramine effectively reduced the magnitude of the histamine wheal in both groups. (3) Isoproterenol decreased the wheal size in both groups. (4) Propranolol increased the wheal size in only the nonatopic group. (5) The successful modulation of the histamine-induced wheal and flare indicated that these drugs, regardless of their effect on the dermal mast cell, exert a measurable effect on the target organ (vasculature).     

Influence of the histamine control on skin reactivity in skin testing

We investigated the effect of the histamine control (1 mg/ml) on the results of skin prick and intradermal testing with bee and wasp venom. Skin tests were done on the patients' forearms: on the right arm the histamine control and the bee venom dilutions, on the left arm the wasp venom dilutions only, at distances of 4-5 cm. In intradermal testing 11 (9%) of 122 patients showed a positive wheal and flare reaction to the bee venom solution positioned next to the histamine control. The subsequent solutions in higher concentrations did not produce any skin reactions. The results of intradermal testing with bee venom did not occur in intradermal testing with wasp venom or in skin prick testing with both allergens. Our results show clearly that in skin prick tests a distance of 4-5 cm is sufficient to avoid false positive skin reactions. However, using the same distance in intradermal testing showed that histamine affects the skin reactions produced by adjacent allergen solutions. Therefore false positive results may occur.     

Bronchial allergen challenge in subjects with low levels of allergic sensitization to indoor allergens

BACKGROUND: Low skin reactivity to common inhalant allergens is frequently found in asymptomatic individuals as well as in patients with respiratory complaints. However, most studies on bronchial allergen challenge concern patients with high levels of allergic sensitization. The present study was directed to bronchial reactions after allergen challenge in subjects with low skin reactivity to Dermatophagoides pteronyssinus or cat dander. METHODS: Titrated intracutaneous skin tests, skin prick tests, specific IgE assays, histamine release on washed leukocytes, and bronchial histamine and allergen-challenge tests were performed in 20 subjects with an intracutaneous skin test threshold for cat dander (Felis domesticus) or D. pteronyssinus above 0.1 BU/ml (mean wheal diameter in skin prick test with 10000 BU/ml: 4.4mm). Ten of the 20 patients had specific IgE below the detection limit in at least one of the three IgE assays which were done. Fifteen patients had a specific IgE level below 2 kU/I in all three tests. As a positive control group, the same parameters were studied in seven moderately sensitized patients with an intracutaneous skin test threshold below 0.1 BU/ml (mean wheal diameter with 10000 BU/ml: 7.2mm). RESULTS: The 20 subjects with low levels of allergic sensitization had an early decrease in FEV1 of 8.6% (P<0.01) and a mean late decrease of 6.3% (P<0.05). There was a trend for decrease in PC20 histamine 24h after allergen challenge (-0.4 doubling doses, P=0.09). CONCLUSIONS: In this group of subjects with low levels of allergic sensitization, a statistically significant early and late decrease in FEV1 was found. However, the decrease in lung function was small and unnoticed by most patients. The increase in nonspecific bronchial hyperresponsiveness after bronchial allergen challenge did not reach statistical significance in the study group. The results indicate that allergen exposure in patients with low levels of allergic sensitization may lead to airways changes in the absence of acute symptoms.     

Skin reactivity to histamine and codeine in unselected 9-year-old children from Italy, Poland and Libya

BACKGROUND: Previous studies have shown that histamine skin reactivity (the dimensions of a skin wheal elicited by a prick with histamine 10 mg/ml) in unselected school children has increased in Italy during the past two decades and is higher in Italy than in Poland. Hence this variable can probably be influenced by a changing or different lifestyle. The aim of this study was to compare skin reactivity to histamine and codeine (a marker of histamine releasability from mast cells) in schoolchildren from countries with different lifestyles. METHODS: Six previously unstudied unselected populations of 9-year-old schoolchildren (two each from Poland, Italy, and Libya; n = 863 subjects; 49.0% males) were pricked with two concentrations of histamine (10 and 1 mg/ml) and codeine (90 and 9 mg/ml). RESULTS: The higher concentrations of both pharmacologic agents tested yielded significantly different wheal areas in the three countries: Poland < Italy < Libya (histamine, 11.8, 16.1 and 20.7 mm2; codeine, 9.2, 13.2 and 16.2 mm2; p < 0.001 for all comparisons). The lower concentrations elicited almost matching results. Histamine wheal areas correlated closely with areas elicited by codeine in the same individual: angular coefficients of the histamine to codeine regression lines were 0.535, Italy; 0.551, Libya; 0.612, Poland; and 0.581 for the whole population. More histamine was needed to produce a wheal in Poland than in Libya: a 20-mm2 wheal required an injected histamine concentration of about 8.8 mg/ml in Libya, 29.5 mg/ml in Italy and 102.1 mg/ml in Poland. CONCLUSION: More studies are necessary to explain the observed international differences in skin histamine reactivity and their effect on the prevalence of positive allergen skin tests.     

Wheal and flare responses to muscl relaxants in humans

Chemically and pharmacologically unrelated molecules release histamine in humans to produce both cutaneous and systemic responses. It has been suggested that molecular changes in the new benzylisoquinoline-derived muscle relaxant, atracurium, make it less likely to cause histamine release. We therefore injected volunteers intradermally with equimolar concentrations of various muscle relaxants, morphine, papaverine (a benzylisoquinoline), and histamine, to evaluate the relative ability of these drugs to cause wheal and flare responses, and mast-cell degranulation. There were no significant differences in wheal and flare responses among the three benzylisoquinoline-derived muscle relaxants,d-tubocurarine, metocurine, and atracurium. The cutaneous effects of morphine were significantly greater than those of the benzylisoquinoline muscle relaxants, suggesting both direct vascular changes and histamine release. Papaverine injection was followed by a significant wheal but no flare. Skin biopsies from vecuronium- and papaverine-induced wheals revealed normal intact mast-cell granules, suggesting a direct cutaneous vascular response rather than histamine release. Skin biopsies after morphine and atracurium injections revealed mast-cell degranulation. All evaluated benzylisoquinoline muscle relaxants are equipotent histamine releasers at equimolar concentrations. A hydrogenated, benzylisoquinoline-nitrogen-containing ring, present in atracurium but not in papaverine, appears to be the molecular conformation responsible for mast-cell degranulation by atracurium.     

Clinical application of histamine prick test for food challenge in atopic dermatitis.

Determining positive food challenges are not easy as there is an absence of simple and objective tests. Histamine, an essential mediator for allergic reactions, is involved in the pathogenesis of atopic dermatitis (AD) and food challenges can change histamine levels. The significances of a prick test with histamine (histamine prick test, HPT) relating to the interpretation of food challenges in AD were evaluated. A total of 467 AD patients participated in this study. Skin prick tests, identification of specific IgE and open food challenge were conducted for the identification of food allergy. Elimination diet was performed with HPT. HPTs were conducted before and after food challenges. The wheal sizes by HPT were significantly decreased after an elimination diet. The relative changes of wheal sizes significantly correlated with those of clinical severity scores in AD patients (p<0.001). The wheal sizes in HPT were increased with a positive provocation in open food challenges. In conclusion, HPT may be a simple and objective test to interprete the results of food challenges in patients with AD. The exact mechanisms of the changes in skin reactivity by HPT need further investigation.     

Non-specific histamine release activity of busereline, LH-releasing hormone

Busereline acetate is an LH-RH agonist that was found to induce local reactions at the injection site or generalized minor skin reactions in some patients. Since these reactions may represent the first reaction of systemic anaphylaxis, we tested the non-specific histamine releasing activity of this drug by intradermal skin tests. It was found that all subjects tested had a positive wheal and flare reaction, the flare being significantly decreased by terfenadine. Benzyl alcohol, the preservative used in commercial preparation of busereline acetate, did not elicit a positive wheal and flare reaction in two patients who had experienced a clinically noticeable reaction. It is concluded that busereline is likely to be a non-specific histamine releasing compound.     

Changes over 13 years in skin reactivity to histamine in cohorts of children aged 9-13 years

BACKGROUND: Several studies report substantial differences in the prevalence of skin test reactivity to allergens in children from adjacent geographic areas; others report an increased prevalence over time. To find out whether these differences depend on variations in skin reactivity to histamine, we determined the time trend of histamine wheal sizes in successive cohorts of unselected children living in the same area (Viterbo, Italy). METHODS: We conducted three epidemiologic surveys, each including children aged 9 and 13 years. The 1983-7 study investigated 170 children (150 were tested twice); the 1992 study, 158 children; and the 1996 study, 208 children. RESULTS: In both age groups, the mean diameter of the wheal induced by histamine skin prick tests (10 mg/ml) increased significantly over time (9-year-olds: 3.25 mm in 1983, 4.68 in 1992, and 5.89 in 1996; 13-year-olds: 3.89 mm in 1987, 5.18 in 1992, and 6.50 in 1996) (P < 0.001 between subsequent studies). The distribution of the wheal diameters for both ages showed a trend to a right shift in the three successive studies (P < 0.001). The dose-response curves for three histamine concentrations (0.2, 1, and 10 mg/ml) had significantly steeper slopes in 1996 than in 1983-7 (P < 0.001). CONCLUSION: The marked time-related increase in the size of the histamine wheals could help to explain the trend toward an increased prevalence of positive allergen skin test reactions reported during the past years. The causes of increased skin reactivity to histamine remain conjectural.     

Measurement of interstitial cetirizine concentrations in human skin: correlation of drug levels with inhibition of histamine‐induced skin responses

BACKGROUND: The purpose of the present study was to measure the concentrations of cetirizine in the extracellular water compartment in intact human skin and assess simultaneously inhibition of histamine-induced wheal and flare reactions. METHODS: Skin cetirizine levels were collected by the microdialysis technique and analyzed by high-pressure liquid chromatography with mass spectrometry detection. Skin levels in 20 subjects were compared to plasma levels for 4 h after a single oral dose of 10 or 20 mg of cetirizine. Skin prick tests were performed with histamine 100 mg/ml. RESULTS: Plasma cetirizine levels increased within 30 min to reach peak values of 315+/-10 and 786+/-45 ng/ml 90-120 min after administration of 10 and 20 mg of cetirizine. This was followed by a slow decline. In the skin, dialysate cetirizine levels (non-protein-bound fraction only) peaked at 1.6+/-0.1 and 2.4+/-0.3 ng/ml at 120-180 min. In vivo recovery of cetirizine was 14.4+/-4.3%. It was estimated that the non-protein-bound concentration of cetirizine in the skin was 50-70% of corresponding plasma values. Both 10- and 20-mg doses of cetirizine inhibited wheal and flare reactions over 240 min. The time vs concentration profile of cetirizine in skin dialysate paralleled the inhibition of skin reactions, but no significant correlations were found between individual cetirizine levels in skin or plasma with wheal and flare reactions. CONCLUSIONS: Cetirizine concentrations in the skin could be monitored by the microdialysis technique. The results indicate no simple linear correlation between cetirizine skin levels and inhibition of skin reactions.     

The effects of butterbur on the histamine and allergen cutaneous response.

BACKGROUND: Butterbur or Petasites hybridus is an herbal remedy that exhibits antihistamine and antileukotriene activity and has been shown to attenuate the response to adenosine monophosphate challenge in patients with allergic rhinitis and asthma. However, no data are available regarding its effects on the histamine and allergen cutaneous response. OBJECTIVE: To evaluate the effects of butterbur compared with fexofenadine and montelukast on the histamine and allergen wheal and flare cutaneous responses. METHODS: Atopic patients were randomized into a double-blind, double-dummy, crossover study to receive for 1 week butterbur, 50 mg twice daily (8 AM and 10 PM); fexofenadine, 180 mg once daily (10 PM), and placebo once daily (8 AM); montelukast, 10 mg once daily (10 PM), and placebo once daily (8 AM); or placebo twice daily (8 AM and 10 PM). Patients attended the department at 10 AM and had measurements of the cutaneous wheal and flare responses to histamine, allergen, and saline control at 10-minute intervals for 60 minutes. RESULTS: Twenty patients completed the study. The mean +/- SE histamine wheal and flare responses, respectively, were significantly attenuated (P < .05) by fexofenadine (9.4 +/- 1.8 mm2 and 13.5 +/- 3.2 mm2) compared with placebo (15.5 +/- 3.3 mm2 and 179.8 +/- 74.3 mm2) but not by butterbur (16.4 +/- 2.1 mm2 and 297.7 +/- 121.2 mm2) or montelukast (19 +/- 1.9 mm2 and 240.2 +/- 66.6 mm2). The allergen wheal and flare responses, respectively, were also significantly attenuated (P < .05) by fexofenadine (31.1 +/- 6.3 mm2 and 256.9 +/- 86.5 mm2) compared with placebo (65.4 +/- 15.2 mm2 and 1,014.5 +/- 250.0 mm2) but not by butterbur (50.4 +/- 9.2 mm2 and 1,110.3 +/- 256.1 mm2) or montelukast (58.8 +/- 9.1 mm2 and 1,463.6 +/- 295.6 mm2). CONCLUSIONS: Butterbur did not produce any significant effects on the histamine and allergen cutaneous response compared with placebo, whereas mediator antagonism with fexofenadine but not montelukast produced significant attenuation. This finding would suggest that butterbur may not be effective in allergic skin disease.     

Skin prick test responses to codeine, histamine, and ragweed utilizing the Multitest device

Epicutaneous skin testing is a useful diagnostic tool in evaluating allergic disorders. Utilizing the Multitest device, skin prick test responses to codeine phosphate, histamine phosphate, and ragweed were examined in 56 human subjects. Relationships between the two positive controls, codeine and histamine, and their use as a reference denominator for ragweed reactions were assessed. Ragweed elicited detectable wheals in 15/56. Histamine phosphate (2.75 mg/mL) elicited a positive wheal response in 52/56 subjects, while codeine phosphate elicited a positive wheal in 39/56 and 30/56 subjects at 30 and 3 mg/mL, respectively. Wheal sizes for codeine phosphate at both 30 and 3 mg/mL showed significantly concordant relationships with histamine phosphate-induced wheal sizes (Spearman rho, P = .0084 and .0155, respectively); however the intersubject coefficient of variation was lower for histamine-induced wheal sizes (44%) than for codeine-induced wheal sizes (64% and 65%, respectively for 30 and 3 mg/mL). When a ratio of allergen to positive control reaction size was used to grade ragweed reactions, different patterns were observed using codeine compared with histamine. These results have implications in utilizing codeine phosphate as a positive skin prick test control for allergy testing.     

Histamine is released in the wheal but not the flare following challenge of human skin in vivo: a microdialysis study

Background The mediator mechanisms of the cutaneous wheal and flare response, which underlies allergic skin and urticarial conditions, are controversial. The wheal results primarily from a direct effect of histamine on the local vascular bed, but to what extent does histamine diffuse within the wheal? The flare is neurogenic in origin, being disseminated within the dermis by axon reflexes, but do the neuropeptides released from the nerve endings cause the vasodilatation directly or do they induce the further release of histamine which then transduces the fiare? Objective We have addressed these questions by inserting 216 μm diameter microdialysis fibres into the dermis within the different areas of the wheal and flare to monitor changes in histamine levels provoked by intradermal injections of histamine, allergen, codeine and substance P. Twenty-one subjects participated in the investigations. Results The histamine concentration in unprovoked skin was 10.5 ± 0.6 nM. As the dialysis efficacy was 50%, this equates to tissue concentrations of 20 nM. All provicants released large amounts of histamine at the injection site, maximum histamine levels being 337–1293 nM. Diffusion of histamine within the wheai was poor, levels at 2.3 mm and 3.7 mm from the site of injection being 4–22% and 0.2–3.7% respectively of those 1 mm from the injection site. No increased histamine levels were detected in the flare with any provicant. Atraumatic delivery to the skin of histamine in infusion concentrations of 30–10000 nM caused concentration-related effects, at least 100 nM being necessary to induce a significant increase in skin blood flow, a threshold of 300–1000 being required to stimulate a visible flare and a measurable erythema, and 3000–10000 nM being the minimum for induction of a wheal. Thus the skin blood vessels and nerves are responsive to histamine, but at relatively high concentrations Conclusions These data support the theory that the flare reaction to local histamine injection or release is a neurogenic reflex not involving histamine release at its effector end.     

Suppressive effects of histamine skin reactivity by a nonsedating antihistamine-mequitazine.

The suppressive activity of mequitazine (MQZ) on histamine skin reactivity was evaluated in 29 healthy subjects (age 22-25 years) in a single-blind study. Fifteen subjects received MQZ, at a dosage of 5 mg BID, for 7 days while 14 served as controls. A prick skin test with saline or histamine hydrochloride (1 mg/ml and 10 mg/ml) was performed in duplicate, on both forearms, starting from the baseline day and continuing for 4 days after medication had been discontinued (total of 11 days). The skin-test subject and the reader was unaware of the randomization process. Mean diameters of wheal and flare as well as the skin index scores (after Voorhost) were used in the analysis. Maximal flare suppression (as compared to the baseline values) was observed on day 6 (97% suppression for 1 mg/ml and 54% suppression for 10 mg/ml, p less than 0.01). Suppression of wheal size was significant (19% for 1 mg/ml and 28% for 10 mg/ml) but was not clinically relevant. Suppression of skin index scores was maximal on day 6 (71% for 1 mg/ml and 43% for 10 mg/ml, p less than 0.01). After MQZ had been discontinued, all measurements gradually returned to baseline values and were not different therefrom within 3 days. However, final measurements of wheal and flare were smaller than baseline values (60-94% of baselines). We conclude that MQZ, at the manufacturers's recommended dose of 5 mg BID, significantly suppressed flare size of histamine skin tests and recommend that MQZ be discontinued for at least 3 days prior to performing allergy skin tests.