Effect of terbutaline and bambuterol on immediate-type allergic skin responses and mediator release in human skin

Background: Beta-2 agonists are potent inhibitors of mast cell degranulation in vitro. Intradermally injected they also inhibit mast cell activation in human skin in vivo. To what extent orally administered ₂-agonists inhibit mast cell degranulation and allergic skin responses in vivo in daily recommended doses remains unclear.Purpose: The main purpose was to study the effects of oral administered terbutaline and bambuterol on allergen- and codeine-induced histamine release and skin responses in intact human skin in vivo. In addition, control studies were carried out with intradermally injected terbutaline.Methods: Ten allergic subjects were randomized to receive bambuterol (10 mg tablets twice daily), terbutaline (7.5 mg controlled release tablets twice daily) and corresponding placebo for 5 days with a washout phase of 3 days between treatments in a double-blind, double-dummy, cross-over trial. The patients were studied at the fifth day of each regimen, i.e. at day 5, 13, and 21. Allergen- and codeine-induced histamine release was measured by microdialysis technique. Wheal and flare reactions to allergen, codeine, and histamine were measured planimetrically. Measurements were performed in the morning on day 5 on each regimen before medication and for additional 5 h after administration of the morning dose. In a separate series of experiments in another 10 allergic patients, 1–1,000 nM (0.05–50 pmoles) of terbutaline was injected intradermally for measurement of histamine release, prostaglandin D2 (PGD2) synthesis and skin responses.Results: Neither orally administered terbutaline nor bambuterol significantly reduced allergen- or codeine-induced histamine release. Flare reactions to allergen, codeine and histamine remained unaffected which was also the case for the majority of the wheal reactions. In comparison, intradermally injected terbutaline significantly reduced allergen-induced histamine release, PGD₂ synthesis, and skin reactions. Codeine-induced histamine release remained unaffected. Terbutaline significantly reduced flare reactions to codeine and histamine with no effect on wheal reactions.Conclusions: Terbutaline, in micromolar concentrations, was a potent inhibitor of immediate allergic skin reactions primarily due to inhibition of mast cell degranulation. However orally administered terbutaline, as the active drug itself or released from its pro-drug bambuterol, did not inhibit mast cell activation or allergic skin responses. Received 28 January 2003; returned for revision 7 March 2003; accepted by M. Parnham 29 April 2003     

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.     

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.     

Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine

Single-dose salbutamol (200 micrograms), beclomethasone dipropionate (200 micrograms), and sodium cromoglycate (SCG) (10 mg) administered by inhalation 10 minutes before allergen challenge were examined with regard to inhibition of allergen-induced early (EAR) and late (LAR) asthmatic responses and allergen-induced increase in bronchial responsiveness to inhaled histamine. Ten atopic subjects with asthma participated in a blinded, crossover, placebo-controlled trial. The EAR was inhibited by salbutamol and SCG but not by beclomethasone dipropionate or placebo (p less than 0.01). The LAR (p less than 0.01) and the allergen-induced increased bronchial responsiveness to histamine 7 hours (p less than 0.01) and 30 hours (p less than 0.05 and p less than 0.01 for various comparisons) were inhibited by SCG and beclomethasone diproprionate but not by salbutamol or placebo. The allergen-induced LAR and associated increased responsiveness are now believed to be more important clinically than the EAR. The clinical relevance of these results is to stress the importance of the prophylactic nonbronchodilator drugs (SCG and steroids) and the potential inadequacy of bronchodilators used alone in the treatment of both perennial and seasonal allergic asthma.     

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.     

Effects of cromolyn on codeine-induced histamine release in vivo

Cromolyn has been shown to inhibit histamine release from mast cells induced by various stimuli in vitro. However, the local effects of cromolyn on codeine-induced wheal and flare skin reactions are not well understood. Intradermal injection of codeine induced prominent whealing in almost all humans. We studied the effect of local cromolyn injection on codeine-induced skin reactions, histamine release, and ultramicroscopic changes in mast cells in 10 volunteers. The finding in this study showed that injection of a 2% cromolyn solution before or together with the codeine injection does not affect the subsequent skin reactions, histamine release and ultramicroscopic changes of mast cells.     

Effects of salmeterol and terbutaline on IgE-mediated dermal reactions and inflammatory events in skin chambers in atopic patients

The objective of the present study was to investigate the potential of the long-acting p-aonist salmeterol as an inhibitor of various components of IgE-mediated inflammation in man. For this purpose, we measured gross skin reactivity (diameters of wheal and flare reaction [WFR] and late cutaneous reaction [LCR]) as well as inflammatory cells, mediators, and protein in cutaneous suction blister chambers in eight subjects with allergic rhinitis. Blisters were induced, two on each forearm, by gentle suction and heating, and were unroofed 12 h later, after which plastic chambers were placed over the denuded area. The chambers were challenged for 2 h with antihuman IgE (titer 1:10) in the presence and absence of salmeterol or terbutaline. Normal goat IgG served as negative control. Chamber fluids were removed hourly for the first 4 h, and this was followed by a 4-h incubation before final collection. Salmeterol (10^-6M) and terbutaline (10^-5 M) injected intradermally 30 min before, as well as together with anti-IgE (titer 1:100), inhibited the WFRs by up to 30%. The effect of salmeterol on the ensuing LCR (75% inhibition at 24 h) tended to be more pronounced than the corresponding inhibition by terbutaline. Both salmeterol and terbutaline very effectively inhibited the anti-IgE-induced extravasation of α₂-macroglobulin into skin chambers, with a significantly more sustained effect by salmeterol. Interestingly, only terbutaline reduced the histamine release evoked by anti-IgE. With the present experimental design, where both drugs were washed out from the chambers after 2 h, neither drug inhibited recruitment of leukocytes (including eosinophils). Taken together, salmeterol had a more sustained inhibitory effect than terbutaline on indices of IgE-mediated edema formation (late induration and plasma protein extravasation). On the other hand, under the present experimental conditions, salmeterol failed to reduce the histamine release (in contrast to terbutaline), and neither salmeterol nor terbutaline affected the recruitment of leukocytes.     

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.     

A naturally occurring opioid peptide from cow's milk, beta-casomorphine-7, is a direct histamine releaser in man.

beta-Casomorphine-7, a naturally occurring product of cow's milk with opiate-like activity, was studied for possible direct histamine liberation activities in humans. It was found to cause concentration-dependent in vitro histamine release from peripheral leukocytes of healthy adult volunteers. Intradermal injection of beta-casomorphine-7 induced a wheal and flare reaction in the skin similar to histamine or codeine. Oral pretreatment with the H1 antagonist terfenadine significantly inhibited the skin responses to beta-casomorphine-7. The intradermal injection of an opiate receptor antagonist, naloxone, inhibited in vitro histamine release and skin reactions only in a 100-fold excess over beta-casomorphine-7. These findings suggest that beta-casomorphine-7 can be regarded as a noncytotoxic, direct histamine releaser in humans. The clinical relevance of these findings deserves further studies.     

Quantitative skin prick testing

Dose-response curves of histamine- and allergen-induced wheal areas were evaluated in seven normals (defined as negative skin prick test (SPT) to inhalant allergens and no clinical signs of allergy), seven latent allergics (positive SPT without allergic symptoms), and 20 manifest allergics (positive SPT and allergic symptoms). Three concentrations of histamine HCl (1, 10 and 100 mg/ml) and three 10-fold concentrations of nine inhalant allergens (birch, timothy, mugwort, horse, dog, cat, house dust mite, Cladosporium and Alternaria) in concentrations 1,000 10,000 and 100,000 BU/ml were used and linear regression was performed on the skin reactions. Only tests with an SD% less than 40%, a log slope greater than 0.1, and a correlation coefficient greater than 0.95 were accepted. In normals a significantly higher concentration of histamine was needed to elicit a wheal reaction of 2 mm2 (end-point) compared with allergics. Likewise, normals had a significantly higher slope i.e. steeper dose-response curve of histamine than manifest allergics. The slope of the allergen-induced wheal area was significantly higher than the histamine slope. No relation between corresponding slope of histamine and allergens was found (Rho = 0.15). The skin sensitivity equivalent to histamine calculated as the allergen concentration eliciting a wheal equal to histamine showed a median increase of 5-6 fold in allergen concentration by a 10-fold increase of histamine concentration. The highest correlation between the wheal area of a single allergen concentration and the skin sensitivity was found for allergen concentration 100,000 BU.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of loratadine on anti-IgE-induced inflammation, histamine release, and leukocyte recruitment in skin of atopics

The aim of this study was to assess the ability of the H¹-receptor antagonist loratadine to modify anti-IgE-induced cutaneous wheal-and-flare and late-phase reactions (WFR and LPR), as well as histamine release and leukocyte accumulation in skin chambers. For this purpose, 10 atopics with allergic rhinitis were entered into a double-blind crossover study in which they received either placebo or loratadine (20 mg/day orally) for 8 days separated by a 7-day washout period. Blisters were induced on both forearms on day 7 of each treatment period, and were unroofed on day 8 and covered with plastic skin chambers. Chamber fluids were collected during 7 h after 1-h incubation with anti-IgE or control IgG. Intradermal challenge with histamine and anti-IgE was performed at the same occasion. As compared to placebo treatment, loratadine inhibited the immediate WFRs to anti-IgE by 35% (wheal) and 65% (flare), respectively (P < 0.01), and corresponding reactions to histamine challenge by 50% and 70% (P<0.001), respectively. Moreover, the initial phase (0-2 h) of the LPR induced by anti-IgE was attenuated by up to ～60% (P < 0.001) during loratadine treatment. Thereafter, no inhibition of the LPR was observed. The magnitude and time course of histamine release into skin chambers was virtually the same after loratadine and placebo treatment, with a peak during 0-1 h and a progressive decline during the following 2 h. Accumulation of α2-macroglobulin, reflecting extravasation of large plasma proteins, also peaked during the first hour and was unaffected by loratadine during the 8-h observation period. Moreover, loratadine did not reduce the anti-IgE-induced recruitment of eosinophils or other subtypes of leukocytes. Altogether, loratadine inhibited both the WFRs to histamine and anti-IgE and the initial phase of the IgE-mediated LPR. However, loratadine did not express anti-inflammatory activity with respect to mast-cell mediator release or leukocyte recruitment. The latter findings are in contrast to the action of loratadine in allergic rhinitis and conjunctivitis, suggesting that the actions of loratadine may be organ specific and that the effects of loratadine cannot always be extrapolated from one tissue to another.     

Histopathological Support of Antagonism of Allergen-Induced Mast Cell Mediator Release in Human Skin by a Beta2-Agonist

The site of antagonistic action on allergen-induced early skin reactions by the beta 2-agonist terbutaline was studied by light microscopy in 10 atopic subjects. Pretreatment with 1 microgram terbutaline intradermally 5 min prior to challenge with horse dander allergen produced an approximate inhibition of 85 and 55% of flare and wheal responses respectively (P less than 0.001). Biopsy specimens obtained from skin sites injected with allergen alone showed a reduced number of remaining stainable mast cells as compared to sites injected with terbutaline prior to allergen (P less than 0.05, Sign test). The data support the concept of in vivo inhibition of the mast cell mediator release reaction in atopic skin by terbutaline.     

Skin reactions to histamine of healthy subjects after hypnotically induced emotions of sadness, anger, and happiness

BACKGROUND: The severity of symptoms in asthma and other hypersensitivity-related disorders has been associated with changes in mood but little is known about the mechanisms possibly mediating such a relationship. The purpose of this study was to examine the influence of mood on skin reactivity to histamine by comparing the effects of hypnotically induced emotions on flare and wheal reactions to cutaneous histamine prick tests. METHODS: Fifteen highly hypnotically susceptible volunteers had their cutaneous reactivity to histamine measured before hypnosis at 1, 2, 3, 4, 5, 10, and 15 min after the histamine prick. These measurements were repeated under three hypnotically induced emotions of sadness, anger, and happiness presented in a counterbalanced order. Skin reactions were measured as change in histamine flare and wheal area in mm2 per minute. RESULTS: The increase in flare reaction in the time interval from 1 to 3 min during happiness and anger was significantly smaller than flare reactions during sadness (P<0.05). No effect of emotion was found for wheal reactions. Hypnotic susceptibility scores were associated with increased flare reactions at baseline (r=0.56; P<0.05) and during the condition of happiness (r=0.56; P<0.05). CONCLUSION: Our results agree with previous studies showing mood to be a predictor of cutaneous immediate-type hypersensitivity and histamine skin reactions. The results are also in concordance with earlier findings of an association between hypnotic susceptibility and increased reactivity to an allergen.     

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.     

Terbutaline modulation of human allergic skin reactions

Terbutaline, a preferential beta 2-adrenergic agonist, has been shown to inhibit allergen-induced histamine release in vitro. In contrast, orally administered therapeutic doses of terbutaline do not inhibit antigen-induced wheal and flare reactions. We studied the effects of local terbutaline on antigen-induced whealing response, histamine release, cellular inflammatory response, and ultramicroscopic mast cell changes in antigen-challenged skin sites in ragweed-sensitive subjects. Results showed that ragweed challenge significantly induced increased histamine release in all subjects. In contrast, no such histamine release was observed at sites challenged with antigen in the presence of terbutaline. Thus locally applied terbutaline in nontoxic doses modulates mediator release in certain allergic reactions.     

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.     

Inhibition of allergen-induced early reactions in atopic skin by salbutamol and theophylline

The possible antagonistic effect of the beta₂-adrenoceptor agonist salbutamol and the methylxanthine theophylline on allergen-induced immediate skin reactions was elucidated. Dose-dependent reductions of early allergen-induced responses (flare and weal) were produced in eight atopic patients by salbutamol, 2.5 ng-1 g (p<0.001). Theophylline attenuated these responses only at a high dose, 100 g (p<0.01). Histamine-induced flare responses were not influenced by these agents, but wealing was inhibited by 35% by 1 g of salbutamol (p<0.001). It is concluded that agents which interact with anaphylactic histamine release and elevate cyclic AMP level in heterogenous tissuesin vitro have similar counteracting effects on allergen-induced skin reactions in atopic subjects.     

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.     

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)     

Effects of local treatment with salmeterol and terbutaline on anti-IgE-induced wheal, flare, and late induration in human skin

The capacity of terbutaline and the long-acting β₂-agonist salmetcrol to suppress wheal-and-flare reactions (WFRs) to intradermal antihuman IgE and to histamine was evaluated in 36 healthy volunteers. We also exaniined effects of the two drugs on the subsequent late cutaneous reaction (LCR) to anti-IgE. Salmeterol (10^-10 10^-6 M) and terbutaline (10^-10 10^-5 M), injected intradermally 2 or 15 min before anti-IgE challenge, produced a dose-dependent inhibition of the WFRs to anti-IgE (liter 1:10000) with a maximal effect of ?60% (wheal) and ??75% (flare) by both drugs. On a molar basis, salmctcrol was approximately 10–100 times more potent than terbutaline in inhibiting the WFRs. Moreover, the wheal response to histamine (4 nmol) was antagonized by ?40% after prctrcatment with either salmeterol (10^-5 M) or terbutaline (10^-4 M). We found that both salmeterol and terbutaline exhibited anti-WFR activity for up to 24 h, salmeterol being significantly more potent in this regard. When selecting a 15-min pretreatment interval with equieffective anti-WFR doses from the first dose-response experiments (i.e., a salmetcrol: terbutaline ratio of 1:10), the WFRs to high-dose anti-IgE (titer 1:100) were inhibited by terbutaline (10^-5 M) by 25–30%, but not by salmeterol (10^-4). On the other hand. salmeterol attenuated (by up to ?35%) the subsequent LCR more effectively than terbutaline. As compared to the prctrcatment procedure, infiltration of the drugs (single doses) into the wheals 30 min after challenge with anti-IgE (titer 1:100) proved to be less effective on the development of LCRs. Taken together, salmeterol was found to express higher potency and have longer duration of action than terbutaline in inhibition of IgE-mediated inflammation in human skin.