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.     

Twelve months, treatment with inhaled salmeterol in asthmatic patients

Salmeterol is a new beta 2-receptor agonist with a prolonged duration of action after inhalation, exceeding 12 h in most patients. We have performed a 12-month open follow-up study on 11 patients with reversible asthma. All patients were given salmeterol inhalations (50 micrograms twice daily). Additional asthma treatment included inhaled corticosteroids in all patients, and oral slow-release theophylline or beta 2-receptor agonists in a minority of patients (3 and 1, respectively). Before salmeterol treatment was initiated and after 3, 6, 9 and 12 months of salmeterol treatment, a cumulative dose-response curve to inhaled salbutamol (100, 300 and 900 micrograms) was performed, and FEV1 measured. We also evaluated the effect of each salbutamol dose on finger tremor, systemic blood pressure and heart rate. Blood tests, including white blood count and electrolytes, were taken at each visit. After salmeterol treatment was initiated, morning FEV1, measured before the morning asthma medication, was significantly improved (p < 0.05). The responsiveness to inhaled salbutamol was not decreased during salmeterol treatment, except in one patient with asthma worsening over the study year. Baseline finger tremor measured before salbutamol dose-response curves, was significantly lower at the 12-month visit than before treatment was initiated (p < 0.05). Effects of salbutamol on systemic blood pressure, heart rate or finger tremor was not significantly changed during salmeterol treatment. We found a successive and significant decrease in blood eosinophils (p < 0.05) during the 12 months of salmeterol treatment, when the patient with asthma worsening was excluded in the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

A 4-week comparison of salmeterol and terbutaline in adult asthma*

This was a 4-week, open-label, parallel-group study designed to compare the efficacy and safety of the long-acting inhaled bronchodilator, salmeterol, with the established inhaled bronchodilator, terbutaline, in the treatment of patients with mild to moderate asthma. A total of 243 adult patients was randomized to receive treatment with either salmeterol 50 μg bd via a Diskhaler^TM (Glaxo) inhaler (n=121) or terbutaline 500 μg qds via a reservoir powder inhaler device (n=122). Apart from all bronchodilator treatment which was withdrawn at the start of the run-in period and replaced by inhaled salbutamol to be used as required for symptom relief, all concurrent medications were kept constant throughout the study. Salmeterol produced a significantly greater increase in mean morning peak expiratory flow (PEF) than terbutaline (difference in adjusted means after treatment=28 l/min; 95% CI=19–37 l/min; P<0.001). Likewise, the increase in mean evening PEF was significantly greater following treatment with salmeterol than with terbutaline (difference in adjusted means=9 l/min; 95% CI=0–17 l/min; P=0.045). Salmeterol was associated with a significant reduction in diurnal variation in PEF by comparison with terbutaline (difference in adjusted means=?18 l/min; 95% CI=?24, ?12 l/min; P<0.001). Significant improvements with salmeterol by comparison with terbutaline were also observed in daytime and night-time asthma scores, percentage of symptom-free days and nights, use of additional inhaled bronchodilator, and percentage of days and nights when no additional inhaled bronchodilator was needed. The greater overall improvement in the control of asthma and its symptoms after treatment with salmeterol was further evident from the lower incidence of asthma-related adverse events in patients taking salmeterol compared with those taking terbutaline (2% and 15%, respectively). While both treatments were well tolerated, more patients withdrew from the terbutaline group than from the salmeterol group (12 and 3 patients, respectively) and terbutaline was associated with a higher incidence of drug-related adverse events (26% and 9% in the terbutaline- and salmeterol-treated groups, respectively). This study demonstrated that salmeterol 50 mUg bd via a Diskhaler was significantly more effective and associated with fewer adverse events than terbutaline 500 μg qds via a reservoir powder inhaler device.     

Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin

BACKGROUND: This randomized, double-blind, crossover study compared the effects of the R-enantiomer of cetirizine, levocetirizine, with those of loratadine on the wheal, flare, and itch response to histamine in human skin. METHODS: Levocetirizine (5 mg), loratadine (10 mg), or placebo was taken orally 4 h before the intradermal injection of histamine (20 microl, 100 microM) or the control vehicle into the forearm skin of healthy volunteers. Flare areas were assessed by scanning laser Doppler imaging before and at 30-s intervals for a period of 9 min. Wheal areas were measured by planimetry at 10 min. Itch was scored every 30 s with a visual analogue scale. RESULTS: After placebo administration, the mean peak flare area was 23.01+/-1.94 cm(2), the wheal area 248+/-27 mm(2), and the cumulative itch score 28.8+/-4.6% (mean+/-SEM). Levocetirizine reduced the flare, wheal, and itch by 60%, 68%, and 91%, respectively (all P<0.001, Student's t-test for paired data). The effects of loratadine were variable and not statistically significant. CONCLUSION: Levocetirizine (5 mg) is a potent inhibitor of the effects of histamine in human skin with an efficacy that exceeded that of loratadine (10 mg) when single doses of the drugs were administered 4 h before the test.     

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.     

过敏原引起的人皮肤晚期反应样本中白细胞介素6和8 mRNA的表达

采用原位杂交技术 ,测定白细胞介素 6 (IL 6 )和白细胞介素 8(IL 8)mRNA在变应原诱导的皮肤晚期反应标本中的表达。 14例标本中 ,两种细胞因子表达的阳性率分别为 12 14和 13 14。与相应对照比较 ,变应原攻击标本中表达上述细胞因子mRNA的阳性细胞数明显增加 (P <0 0 1)。     

Immunohistochemical analysis of late local skin reactions during rush venom immunotherapy.

During rush venom immunotherapy (VIT), about 65% of patients develop large local reactions (LLR) at the application site that last for at least 24 h. However, LLR subside during long-term treatment. To learn more about the provenance of infiltrating cells in late, local skin reactions during VIT, we analyzed the skin infiltrates of 23 Hymenoptera venom (HV)-allergic patients. Punch biopsies were obtained 24 h after s.c. injection of HV allergens from 23 HV-allergic patients and five nonallergic controls. Seven patients did not show LLR at the beginning of VIT. Ten patients had LLR when the dose of HV allergens was increased. Six patients showed reduced LLR after long-term treatment. Immunoenzymatic labeling of the cryostat sections with a panel of monoclonal antibodies was performed by the APAAP method. S.c. application of HV allergens induced a perivascular and periadnexial cutaneous mononuclear cell infiltrate consisting mainly of CD4⁺, CD45RO⁺, and HLA-DR⁺ cells in patients without clinically apparent LLR. In contrast, LLR were associated with a significant increase in total cells, CD4+ cells, CD8+ cells, CD11c⁺ cells, EG2⁺ cells, NP57⁺cells, HLA-DR⁺ cells, CD45RO⁺ cells, CD45RA⁺ cells, CD23+ cells, and CD25⁺ cells (P < 0.001). Decreased LLR after long-term VIT was correlated with a significantly reduced recruitment of CD4⁺ cells, EG2⁺ cells, and CD23⁺ cells as compared to LLR in the course of dose increases (P<0.05), whereas the number of CD8+ cells, CD11c⁺ cells, NP57⁺ cells, and CD25⁺ cells remained high. Our data suggest that s.c. injections of HV allergens attract CD4⁺ helper T cells, of both the naive (CD45RA⁺) and memory (CD45RO⁺) phenotypes, to the allergen application site. LLR represent delayed allergic rather than toxic reactions to HV components and might be relevant to the development of clinical protection during VIT.     

Inhibition of anti-IgE induced skin responsein normals by formoterol, a new β2-adrenoceptor agonist, and terbutaline

Formoterol, a new beta 2-selective long-acting bronchodilator, was compared with terbutaline in terms of ability to inhibit dual phase skin reactions to anti-human IgE in volunteers. Anti-IgE induced an early wheal and flare reaction (WFR) followed by a progressively increasing induration, the late phase reaction (LCR), lasting greater than or equal to 24 h. Intradermal injection of formoterol 20 ng or terbutaline 500 ng 5 min before challenge gave equal inhibition of the WFR. The subsequent LCR was suppressed by formoterol (30%) for the whole 24 h period, while terbutaline only attenuated the first 4 h period. Increasing the dose range of both drugs 25-fold, caused a further analogous reduction of the WFR to anti-IgE. In this higher dose range formoterol (0.5 micrograms) antagonized the following 1-24 h LCR by 50%, while terbutaline (25 micrograms) only attenuated the LCR by an average of 20%, with higher effect in the first 6 h period. The anti-LCR capacity of formoterol was highly superior to that of terbutaline (P less than 0.001). The histamine-elicited wheal response was attenuated by both drugs, but they had no effect on the flare response, favouring an anti-permeability action of both compounds. The data support the concept that terbutaline, given locally in a single dose shortly before challenge, inhibits the mast cell mediator release reaction with limited consequences for the following LCR. In contrast to terbutaline, formoterol exerted a substantial anti-LCR action, probably by interfering with inflammatory mechanisms after the initial mast cell mediator release.     

A comparison of levocetirizine and desloratadine in the histamine-induced wheal and flare response in human skin in vivo

Background The histamine-induced wheal and flare response was used to compare quantitatively the antihistaminic potency of levocetirizine and desloratadine. Methods In this double-blind, placebo-controlled crossover study, 24 healthy male non-atopic volunteers received weekly single doses of 1.25, 2.5 or 5 mg levocetirizine, 2.5, 5 or 10 mg desloratadine, or placebo. Four hours after dosing, histamine (100 mg/ml) skin prick tests were performed on the volar surface of both forearms. The diameters of the wheals and flares were measured 10 minutes later. Sedation was evaluated using a visual analogue scale and a motricity test. The effects of individual drug doses were compared using Student’s t-test for paired data and the overall effects of the two drugs by ANOVA. Results All doses of levocetirizine significantly (P < 0.0001) inhibited both wheals and flares in a dose-related manner. Only the 10 mg dose of desloratadine achieved significant inhibition of response. ANOVA showed levocetirizine to be significantly (P < 0.0001) more active than desloratadine. Neither drug caused significant sedation or loss of motricity. Conclusion Levocetirizine is significantly more effective than desloratadine in inhibiting wheal and flare responses to histamine in human skin in vivo, with 1.25 mg levocetirizine being more effective than 10 mg desloratadine. Received 3 July 2005; returned for revision 9 August 2005; returned for final revision 6 February 2006; accepted by M. Parnham 8 February 2006     

Inhibition of anti-IgE induced skin response in normals by formoterol, a new β2 adrenoceptor agonist, and terbutaline

The intention of the present study was to compare formoterol and terbutaline regarding ability to inhibit immediate wheal and flare responses (WFR) to anti-human IgE with focus on the duration of anti-WFR action. Formoterol is a novel beta 2-adrenergic agonist with a prolonged duration of bronchodilation capacity after inhalation. The drugs injected intradermally 2 min prior to challenge with anti-IgE in volunteers produced a dose-dependent inhibition of the WFR in the range 1pg-100ng (formoterol) and 1ng-1 microgram (terbutaline). Formoterol was 70 times (flare) and 25 times (wheal) more potent (ID40) than terbutaline on a weight basis. The duration of the anti-WFR action for formoterol, injected in a 25 times lower dose than terbutaline, was significantly longer, namely greater than 24 h versus 8 h for terbutaline. The histamine-induced wheal reaction was attenuated by 15% and 25% by terbutaline and formoterol, respectively. The results indicate a higher beta 2-receptor activity for formoterol with respect to inhibition of IgE-dependent mast cell mediator release in addition to an anti-leak effect exerted by both drugs. The prolonged duration of antagonistic effect by formoterol on the WFR to anti-IgE might be due to the lipophilic property of the drug, with an expected higher retention of formoterol at the target tissue compared with the more hydrophilic compound terbutaline.     

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.     

The effect of specific immunotherapy on the expression of costimulatory molecules in late phase reaction of the skin in allergic patients

BACKGROUND: Specific immunotherapy (SIT) modulates immune responses to allergens resulting in improvement of allergic symptoms. However, the mechanisms behind the clinical changes are not clear. Participation of costimulatory molecules on antigen-presenting cells and T cells in the process of antigen recognition is suggested to be of essential importance. The SIT effect on expression of costimulatory molecules has not been earlier examined. METHODS: Forty-one birch-allergic patients were treated with SIT or placebo. After 1 year of treatment skin biopsies were obtained 24 h following allergen challenge. Sections were stained with antibodies against: EG2 (eosinophils), CD4 (T cells), CD68 (macrophages), CD1a (Langerhans cells), CD28 (on T cells) and costimulatory molecules (CD80, CD86). RESULTS: Following allergen challenge number of the CD4(+) and CD68(+) cells increased significantly (P=0.002, 0.0001, respectively) in the placebo, but not in the SIT-treated patients. The difference between groups was significant (P=0.003, 0.01, respectively). The numbers of EG2(+) cells increased significantly in both groups. CD80(+) cell numbers increased in the placebo (P=0.01) but not in the SIT group. The number of CD86(+) cells increased in both groups (placebo, P=0.001; SIT, P=0.01) but significantly less in the SIT group (P=0.05). The numbers of CD28(+) cells increased in the placebo (P=0.001) but remained unchanged in the SIT group. The difference between the groups was significant (P=0.05). CONCLUSION: There were lower numbers of cells expressing costimulatory molecules in SIT-treated than in placebo-treated patients. Decreased costimulation may lead to diminished immune response following allergen exposure. This could be an important factor contributing to the clinical improvement after SIT.     

Comparison of the effects of desloratadine and levocetirizine on histamine-induced wheal,flare and itch in human skin

Objective: A previous study showed the inhibitory effects of loratadine on histamine-induced wheal, flare and itch in human skin to be very variable between individuals. It was hypothesised that this variability may have been due to differences in the rates of metabolism of loratadine to its active form, desloratadine. This double blind, crossover study examined the effects of desloratadine in 12 healthy volunteers. Levocetirizine was used as a comparator. Methods: Desloratadine (5 mg), levocetirizine (5 mg) or placebo was taken orally 4 h before an intradermal injection of histamine (20 l, 100 M) or vehicle control into the forearm skin. Flare areas were assessed by scanning laser Doppler imaging before and at 30 s intervals for a period of 9 min. Wheal areas were measured by planimetry at 10 min. Itch was scored every 30 s for 5 min using a visual analogue scale. Results: Following placebo administration, the mean (± SEM) wheal area at 10 min was 79.3 ± 6.9 mm², mean flare area for the first 5 min following challenge 26.6 ± 2.7 cm², and itch score for the same period 48.5 ± 7.6%. The effects of desloratadine were variable between individuals, mean reductions in the wheal and flare areas being 17% (P = 0.033) and 12% (P = 0.036). Desloratadine did not reduce itch significantly. Levocetirizine was more consistent in its effects, mean reductions in wheal, flare and itch being 51%, 67% 78% respectively (all P < 0.001). Conclusions: A single dose of 5 mg levocetirizine produced more consistent and greater inhibitory effects on histamine-induced wheal, flare and itch than did 5 mg desloratadine. The difference is suggested to reflect the basic pharmacokinetics of the two drugs.Received 21 May 2003; returned for revision 29 May 2003; accepted by M. Parnham 5 June 2003     

Effect of local allergen priming on early, late, delayed-phase, and epicutaneous skin reactions

Allergic disease is reflected in a chronic inflammatory response to an allergen. It is thought that local allergen priming underlies this chronicity. To assess the effect of allergen priming on the amplitude and histologie effect of the allergic reaction, four sequential, intracutaneous skin tests were done with 48-h intervals in 13 patients allergic to the house-dust mite Dermatophagoides pteronyssinus (Dpt). Reactions were measured at 15 min, and at 6, 24, and 48 h. Subsequently, epicutaneous tests were done on Dpt-primed spots (n=5). At 6, 24, and 48 h, reactions increased after priming (P<0.006), with unaltered early reactions. Epicutaneous reactions to Dpt on primed spots were larger than in epicutaneous controls on similarly primed skin. Local intradermal priming results in greater inflammatory responses at both intra- and epicutaneous challenge. This mechanism may explain the chronicity of allergic reactions at epithelial surfaces.     

Effects of Oral Theophylline Combined with Oral and Inhaled β2-Adrenostimulants in Asthmatics

The acute ventilatory, cardiovascular and tremorogenic effect of a high oral dose of terbutaline (5 mg) was compared with that of half the dose (2.5 mg) combined with 280 mg anhydrous theophylline orally in the randomized, double-blind, cross-over study in eight asthmatics. After 120 min, when steady-state bronchodilation was achieved, five terbutaline inhalations (1.25 mg terbutaline sulphate) were added to both treatment regimens. The mean maximum plasma concentration of theophylline was then 7 micrograms/ml (39 mumol/l). Inhalation of a beta 2-adrenostimulant had a very good additional effect without increasing side effects in these patients with good inhalation technique. The oral low-dose combination gave significantly better bronchodilation than the high dose of terbutaline alone and caused significantly less tremor. Although the combination only had an additive bronchodilating effect, it may offer important clinical advantages. If the patient cannot use the metered dose aerosol, an oral low dose combination should be preferred to a single high dose of either theophylline or beta 2-adrenostimulants. In patients with good inhalation technique but not controlled by inhalation from a metered dose aerosol alone, a combination of oral theophylline and terbutaline in "sub-optimal" dose and an inhaled beta 2-agonist in individually titrated optimal dose gave a maximal bronchodilating effect with minimum side effects.     

Inhibitory Effect of KWD 2131, Terbutaline, and DSCG on the Immediate and Late Allergen-Induced Bronchoconstriction

Beta-adrenoceptor stimulants exhibit both bronchodilating and anti-allergic activities. KWD 2131 is a new beta-agonist with preferably anti allergic property. In an earlier study, nebulized KWD 2131 in a non-bronchodilating dose (0.25--0.50 mg) did not give significant protection against immediate reaction. The present study evaluated whether an increased nebulized dose of the new compound (5 mg) could protect against either immediate and/or late responses. The response was compared with a nebulized dose of terbutaline (5 mg) and with twice the recommended dose DSCG (40 mg). The study included 10 patients with known allergic asthma. It was designed as a single-blind cross-over trial with randomized allocation of the drugs. Lung functions were measured spirometrically and by body-plethysmograph; flow volume curves were drawn. KWD 2131 gave no significant protection against immediate reaction. Both terbutaline and DSCG did so, terbutaline being more efficient. Contrary to the beta-agonists, DSCG also gave protection against late response.     

Effects of xiao-qing-long-tang (XQLT) on bronchoconstriction and airway eosinophil infiltration in ovalbumin-sensitized guinea pigs: in vivo and in vitro studies

BACKGROUND: Xiao-qing-long-tang (XQLT sho-seiru-to), a traditional Chinese medicine, has been used to treat patients with bronchial asthma in Oriental countries for several centuries. However, the therapeutic mechanisms of this Chinese medicine remain a matter of considerable debate. Therefore, a series of experiments using ovalbumin-sensitized guinea pigs was performed to elucidate the possible antiasthmatic effect of XQLT. METHODS: The effect of XQLT on ovalbumin-induced airway inflammation in a guinea pig model of allergic asthma was examined, and early and late asthmatic responses were measured in terms of airway resistance and extent of eosinophil infiltration. Furthermore, the bronchorelaxing effect of XQLT was measured in isolated guinea pig trachea. RESULTS: XQLT significantly inhibited the antigen-induced immediate asthmatic response (IAR) and late asthmatic response (LAR) in actively sensitized guinea pigs. Cumulative administration of XQLT caused concentration-dependent relaxation of the carbachol-precontracted guinea pig trachea. The bronchorelaxing effect of XQLT was reversed by ICI-118551, a selective beta2-adrenoceptor antagonist. Furthermore, examination of bronchoalveolar lavage fluid (BALF) revealed that XQLT significantly suppressed the increase in eosinophils (24 h after antigen challenge) in the airway. In addition, XQLT significantly attenuated the increase in eosinophils at 1, 6, 24, 48, and 72 h after antigen challenge when it was administered once daily from the day of sensitization to the day of challenge. Histopathologic examination results showed that XQLT suppressed eosinophil infiltration into lung tissue. CONCLUSIONS: These results demonstrate that the antiasthmatic effects of XQLT appear to be partly mediated by stimulation of beta2-adrenoceptors, leading to bronchorelaxation, and that XQLT inhibits the infiltration of eosinophils into the airway. Thus, XQLT may be useful for the prevention or treatment of asthma.     

A double‐blind, single‐dose, crossover comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine versus placebo: suppression of histamine‐induced wheal and flare response for 24 h in healthy male subjects

BACKGROUND: New H1-antagonists have become available, but there has been no comparison of their potency for inhibiting histamine in the skin. METHODS: Cetirizine 10 mg, ebastine 10 mg, epinastine 20 mg, fexofenadine 60 mg, terfenadine 60 mg, loratadine 10 mg, or placebo was given to 14 healthy male volunteers in a double-blind, crossover randomized manner. Inhibition of the wheal and flare response to epicutaneous histamine phosphate (100 mg/ml) challenge was measured at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h after doses. RESULTS: Epinastine inhibited the wheal and flare after 30 min. Cetirizine commenced acting at 1 h and was superior to other treatments. Ebastine was no better than placebo until 4 h, but was efficacious thereafter until 24 h. Terfenadine induced potent inhibition after 1 h and was superior to its metabolite fexofenadine. Loratadine was the least potent inhibitor. Inhibition of the flare response paralleled the patterns seen for wheals. The rank order for area under the curve (0-24 h) was cetirizine, epinastine, terfenadine, ebastine, fexofenadine, loratadine, and placebo. CONCLUSIONS: The inhibition of histamine effects in the skin may be useful in predicting the clinical utility of newly introduced antihistamines in treating allergic disorders.     

Long-term evaluation of usefulness of skin and incremental challenge tests in patients with history of adverse reaction to local anesthetics

A variety of adverse reactions to local anesthetics has been described, some of which are thought to be allergic. Different protocols of prick and intradermal skin tests as well as subcutaneous challenge tests are used to select a local anesthetic which can safely be used. Their long-term effectiveness has not yet been assessed. Twenty-eight patients with a history of adverse reaction to local anesthetics were evaluated over a 3-year period. Loss of consciousness occurred in eight patients, skin reaction in nine, and vagal symptoms in eight. Various reactions were recorded in the remaining three patients. Rapid spontaneous recovery was the rule, suggesting that immediate allergic reaction and, in particular, anaphylactic reaction were unlikely. Investigation allowed the selection of a tolerated anesthetic in all cases. Reexposure occurred in 19 patients 16–50 months after evaluation and 6.8 ± 5.5 years after the first reaction. No patient presented a second reaction. In conclusion, adverse reactions to local anesthetics seem to be, in most cases, not allergic in nature. Evaluation protocols are effective in selecting an agent susceptible to tolerance, but are time consuming. However, they probably contribute to an important reassurance effect that is likely to increase tolerance to subsequent local anesthetic administration. Simplification of the protocols and better patient selection are proposed.