Allergen-induced Early Asthmatic Responses Research Articles

Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

REGN1908/1909 prevented cat allergen–induced early asthmatic responses in an environmental exposure unit

The dominant allergen in cat dander, Felis domesticus allergen 1 (Fel d 1), is a persistent trigger for allergic rhinitis and asthma symptoms. We evaluated the efficacy of Fel d 1 monoclonal antibodies (REGN1908/1909) in preventing cat allergen-induced early asthmatic responses (EARs) in cat-allergic patients with mild asthma. Patients were randomized to single-dose REGN1908/1909 600 mg (n= 29) or placebo (n= 27). The FEV1 was measured for up to 4 hours in a cat allergen environmental exposure unit up to 85 days after dosing. Assessments included between-group differences in change from baseline in FEV1 area under the curve (AUC; 0-2 hours) and incidence of EAR (FEV1 reduction ≥20%). NCT03838731. Single-dose REGN1908/1909 significantly prevented reductions in FEV1 on days 8, 29, 57, and 85. Most REGN1908/1909 patients did not have an EAR by 4 hours (the last time point tested). In contrast, placebo-treated patients experienced a ≥20% mean FEV1 reduction on days 8, 29, 57, and 85 after dosing, with most experiencing an EAR within 1 hour. REGN1908/1909-treated patients tolerated 3-fold higher allergen quantities (P< .05 at all time points) versus placebo. REGN1908/1909 substantially reduced skin test reactivity to cat allergen versus placebo at all time points tested (nominal P< .001). REGN1908/1909 was generally well tolerated; no serious adverse events or deaths were reported. Single-dose REGN1908/1909 significantly prevented reductions in FEV1 in cat-allergic patients with mild asthma on cat allergen environmental exposure unit exposure at 8 days and up to 85 days after dose.

Muscarinic Receptor Antagonism and Allergen Induced Airway Responses in Allergic Asthma: A Scoping Review

The purpose of this scoping review was to identify existing clinical and basic science knowledge surrounding the effect of muscarinic receptor antagonism on allergen-induced airway responses to inform future clinical research in this area. Multiple advanced searches were performed using the National Library of Medicine PubMed search engine. Each search began with two terms; for example, "atropine and asthma" or "tiotropium and airway inflammation". Results were then further refined to include terms such as "allergen" or "ovalbumin (OVA)". Abstracts of refined searches were reviewed for relevance to allergic asthma and allergen-induced airway responses including the early and late asthmatic responses, airway inflammation and tissue remodelling. There was no restriction regarding publication date. Reference lists of selected papers were also reviewed for relevant publications. Nine human clinical trial publications and fourteen animal model publications were identified. In humans, single dose atropine (n=4), ipratropium (n=4) or oxitropium (n=1) administered pre-challenge produced equivocal effects on allergen-induced early asthmatic responses as reported but favored inhibition in eight of nine studies after re-analyses. Animal model investigations (n=14) showed mostly favorable results, especially with respect to airway inflammation and tissue remodelling, although two studies were negative, and one study showed a worsening in allergen induced airway inflammation following muscarinic receptor antagonism. Existing human and animal model data suggest muscarinic receptor antagonism may be beneficial in preventing allergen induced airway responses in those with allergic asthma. Additional human research utilizing current standardized methodologies is required.

Effect of daily tiotropium on allergen-induced early asthmatic responses and airway inflammation

Long-acting muscarinic antagonists (LAMAs) have been approved as an add-on treatment for moderate-to-severe asthma—tiotropium as an individual inhaler and umeclidinium as a combination inhaler. Data from ovalbumin-sensitized and challenged animals treated with muscarinic antagonists, including tiotropium, reveal reductions in inflammatory markers and allergen-associated changes.1,2 Inhaled muscarinic antagonists may, therefore, protect the airways of patients with allergic asthma through both bronchodilators (ie, decrease the early asthmatic response [EAR]) and anti-inflammatory action (ie, decrease type 2 [T2] eosinophilic airway inflammation).

A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma

BackgroundThis study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model.MethodsThis was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge.ResultsNo significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P = 0.028). This effect was greatest 5 min after start of treatment (P < 0.001). The recovery rate was faster but not significantly so (P = 0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ≥12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P = 0.04) with S1226 compared to the placebo.ConclusionsS1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated.Trial registrationClinicalTrials.gov, NCT02334553. Registered on 12 November 2014.

Thunderstorm asthma: An allergen-induced early asthmatic response

Thunderstorm asthma: An allergen-induced early asthmatic response

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses

Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240mg every 2weeks for 10weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24weeks after the first dose. QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15) that was maximal and approximately 3-fold greater than that of omalizumab (P=.10) and 16-fold greater than that of placebo (P=.0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma.

The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats

BackgroundThe inhalation of allergens by allergic asthmatics results in the early asthmatic response (EAR), which is characterized by acute airway obstruction beginning within a few minutes. The EAR is the earliest indicator of the pathological progression of allergic asthma. Because the molecular mechanism underlying the EAR is not fully defined, this study will contribute to a better understanding of asthma.MethodsIn order to gain insight into the molecular basis of the EAR, we examined changes in protein expression patterns in the lung tissue of asthmatic rats during the EAR using 2-DE/MS-based proteomic techniques. Bioinformatic analysis of the proteomic data was then performed using PPI Spider and KEGG Spider to investigate the underlying molecular mechanism.ResultsIn total, 44 differentially expressed protein spots were detected in the 2-DE gels. Of these 44 protein spots, 42 corresponded to 36 unique proteins successfully identified using mass spectrometry. During subsequent bioinformatic analysis, the gene ontology classification, the protein-protein interaction networking and the biological pathway exploration demonstrated that the identified proteins were mainly involved in glycolysis, calcium binding and mitochondrial activity. Using western blot and semi-quantitative RT-PCR, we confirmed the changes in expression of five selected proteins, which further supports our proteomic and bioinformatic analyses.ConclusionsOur results reveal that the allergen-induced EAR in asthmatic rats is associated with glycolysis, calcium binding and mitochondrial activity, which could establish a functional network in which calcium binding may play a central role in promoting the progression of asthma.

Single-dose desloratadine and montelukast and allergen-induced late airway responses

Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.

Magnitude of late asthmatic response to allergen in relation to baseline and allergen-induced sputum eosinophilia in mild asthmatic patients

Late asthmatic response (LAR) to allergen challenge is a validated method for studying the pathogenesis of and new treatments for asthma in the laboratory. To evaluate the relationship between the magnitude of allergen-induced LAR and clinical and biological determinants, including sputum and blood eosinophil percentages and eosinophil cationic protein concentrations. Thirty-eight untreated mild asthmatic patients (mean age, 21.2 years) were selected for the presence of allergen-induced early asthmatic response (EAR) and LAR. Each patient measured methacholine responsiveness (provocation dose that caused a decrease in forced expiratory volume in 1 second of 20% [PD20FEV1]) at baseline, differential blood cell counts and eosinophil cationic protein levels in blood and induced sputum, and serum neutrophil chemotactic activity at baseline and 24 hours after allergen challenge. A correlation was found between LAR (as area under the curve [AUC]) and sputum eosinophil percentages at baseline (r = 0.51; P = .001) and 24 hours after allergen challenge (r = 0.44; P < .007). Furthermore, we found significant correlations between AUC LAR and AUC EAR, baseline methacholine PD20FEV1, baseline blood eosinophil percentages, and baseline serum neutrophil chemotactic activity. A stepwise multiple regression analysis showed that the stronger determinants of AUC LAR were baseline sputum eosinophilia and AUC EAR. Baseline sputum eosinophilia and functional findings are determinants of the magnitude of allergen-induced LAR.

The links between allergen skin test sensitivity, airway responsiveness and airway response to allergen

The allergen-induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint. We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20-based prediction of allergen PC20 (using methacholine) and a new methacholine PC20-based prediction equation. From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20-based and the new methacholine-based formulae. In single regressions, allergen PC20 correlated with both methacholine PC20 (r=0.25, P=0.0015) and skin test endpoint (r=0.52, P <0.00005). The relationship was improved by multiple regression of log-allergen PC20vs. log-methacholine PC20 and log-endpoint (r=0.61, P <0.00005). The histamine-based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine-based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations. We have confirmed the dependence of the allergen-induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.

Comparison of 3 different doses of budesonide and placebo on the early asthmatic response to inhaled allergen

Background: A simple laboratory method to evaluate relative potency of inhaled corticosteroids in asthma would be valuable. Single-dose studies with the allergen-induced late asthmatic response have failed to show a useful dose-response relationship. Treatment for several days with inhaled corticosteroids will also inhibit the allergen-induced early asthmatic response. Methods: Twelve atopic asthmatic subjects were studied during a season when no medications were required except ipratropium bromide as needed. These subjects had positive allergen and methacholine inhalation tests and FEV 1 greater than 70% of predicted value. A double-blind, randomized, cross-over study compared placebo and budesonide 100, 200, and 400 μg administered by means of Turbuhaler twice daily for 7 days with 6-day washout periods. Methacholine PC 20 was measured before and after 6 days of treatment, and allergen PC 15 was measured after 7 days of treatment. Results: The allergen PC 15 ( n = 11) was significantly larger ( P = .0001) for all doses of budesonide compared with placebo, but there was no significant difference between the 3 doses of budesonide, and no dose response was demonstrated. The methacholine PC 20 was significantly larger after all budesonide treatments compared with placebo ( P = .024), but there was no difference between the 3 doses. There was a progressive increase in the allergen PC 15 chronologically (sequence effect) that was not explained by improvement in FEV 1 or airway responsiveness; sequence effects were not seen for FEV 1 or for pretreatment or posttreatment methacholine PC 20. Statistical adjustment for sequence effect did not alter allergen PC 15 statistics. Conclusion: A 7-day course of budesonide administered by means of Turbuhaler at 200, 400, or 800 μg per day provided marked and significant inhibition of the allergen-induced early asthmatic response compared with placebo. There was, however, no difference between the 3 doses. Therefore this method with these doses is not useful for providing assessment of relative potency. (J Allergy Clin Immunol 1998;102:363-7.)

Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects

Background: The cysteinyl leukotrienes (cysLTs) have been implicated in the pathogenesis of allergen-induced airway responses. The purpose of this study was to evaluate the effects of pretreatment with the cysLT receptor antagonist pranlukast on allergen-induced early asthmatic responses (EARs) and late asthmatic responses (LARs) and on allergen-induced airway hyperresponsiveness (AHR). Methods: Ten atopic, nonsmoking patients with mild asthma and previously demonstrated early- and late-phase allergen-induced asthmatic responses participated in a double-blind, placebo-controlled, cross-over study, comparing treatment with either 450 mg pranlukast given twice daily or placebo for 5.5 days. A methacholine challenge was performed before administration of medication, and the result was expressed as the PC 20. An allergen inhalation challenge was performed on the morning of the fifth day of treatment 2 hours after administration of medication. Methacholine challenges were also performed 2 hours after medication on days 4 and 6 (24 hours before and 24 hours after allergen administration) to examine allergen-induced AHR. Results: Pranlukast attenuated allergen-induced early responses, late responses, and AHR. The mean (SEM) maximal percent fall in FEV 1 from baseline during the early response was 30.0% (5.1%) during placebo treatment and 15.5% (3.5%) during pranlukast treatment (mean difference, 14.5%; 95% confidence interval [CI], 5.3 to 23.7; P = .007), with a mean protection afforded by pranlukast of 48.3%. The mean maximal percent fall in FEV 1 during the late response was 34.7% (5.3%) during placebo treatment and 24.0% (4.4%) during pranlukast treatment (mean difference, 10.7%; 95% CI, 4.1 to 17.3; P = .006), with a mean protection afforded by pranlukast of 30.8%. The mean allergen-induced shift in PC 20 was –1.76 (0.32) doubling doses during placebo treatment and –0.38 (0.31) doubling doses during pranlukast treatment (mean difference, –1.38 doubling doses; 95% CI, 0.44 to 2.32; P = .012), with a mean protection afforded by pranlukast of 78.4%. Conclusion: These results demonstrate that pranlukast can attenuate allergen-induced early and late airways responses and AHR and adds further support for an important role for the cysLTs in mediating allergen-induced asthmatic responses. (J Allergy Clin Immunol 1998;102:177-83.)

274 Comparison of three different doses of budesonide and placebo on the allergen-induced early asthmatic response (EAR)

274 Comparison of three different doses of budesonide and placebo on the allergen-induced early asthmatic response (EAR)

Regular use of inhaled albuterol and the allergen-induced late asthmatic response

Background: We have recently demonstrated that a 2-week course of inhaled albuterol 200 μg four times daily caused a near doubling of the allergen-induced early asthmatic response. We hypothesized that this might extend to the more clinically relevant late asthmatic response. Methods: We studied 11 patients with atopic asthma who were free from all medications including inhaled β 2-agonists for more than 4 weeks. We performed a double-blind, random-order, crossover study, comparing the effect of 1-week treatment periods of albuterol 200 μg four times daily and placebo 2 puffs four times daily on the early and late asthmatic responses to the same dose of allergen. Results: Regular use of albuterol did not influence the baseline forced expiratory volume in 1 second (FEV 1) (3.40 vs 3.42 L, p = 0.84) or the baseline methacholine provocative concentration causing a 20% fall in FEV 1 (PC 20) (geometric mean, 2.4 mg/ml vs 1.9 mg/ml, p = 0.38). However, all aspects of the allergen-induced asthmatic response were increased. After the 1-week albuterol treatment, the early asthmatic response was slightly greater (21.1% vs 17.9% FEV 1 fall, p = 0.26), the late response was greater (23.1% vs 13.2% FEV 1 fall, p = 0.0027), and the allergen-induced increase in airway responsiveness (change in log methacholine PC 20) was greater (0.37 vs 0.20, p = 0.045). Conclusions: One week of albuterol treatment (200 μg four times daily) increased the late asthmatic response and allergen-induced increase in airway responsiveness. This suggests that the combination of regular use of inhaled β 2-agonist and allergen exposure may cause more airway inflammation than allergen exposure alone. ( J Allergy Clin Immunol 1995;96:44-9.)

Duration of preventive effect of inhaled salbutamol on early airway response to allergen in asthmatic subjects

Salbutamol is known to effectively prevent early asthmatic response (EAR) after specific bronchial provocation test (sBPT) in asthmatic subjects, but the time-course of this protection is not known. In this study the effects of 200 μg salbutamol inhaled 2 h before sBPT were compared with 200 μg salbutamol inhaled 10 min before sBPT in eight asthmatic subjects sensitized to Phleum pratensis (PP) or Dermatophagoides pteronyssinus (DP). All subjects showed an EAR (% decrease in FEV 1 from baseline value: 30·4 ± 11%) in a preliminary sBPT performed with cumulated doses of extracts of PP or DP titrated in biological units (BU). Each subject performed, on two different days, in a random, double-blind, cross-over study, two puffs of placebo 2 h before sBPT and two puffs of salbutamol 10 min before sBPT (treatment A) or two puffs of salbutamol 2 h before sBPT and two puffs of placebo 10 min before sBPT (treatment B). Baseline FEV 1 were similar in both tests. In treatment B, 10 min, 1 h and 2 h after salbutamol inhalation, FEV 1 increased significantly with respect to placebo inhalation in treatment A. Ten minutes after salbutamol inhalation in treatment A, FEV 1 became similar to that obtained 2 h after salbutamol inhalation and 10 min after placebo in treatment B. Allergen inhalation induced an EAR in only one out of eight subjects after treatment A, and five of the eight subjects after treatment B. The severity of EAR was significantly greater after treatment A than after treatment B, and the FEV 1 after 10, 15, 30 and 60 min from the end of allergen inhalation was significantly different between two treatments. The protection index was significantly greater after treatment A than treatment B. In conclusion, although salbutamol induces the same bronchodilation either 2 h or 10 min after inhalation, the preventive effect on allergen-induced EAR is present when the drug is inhaled 10 min before sBPT, but is less effective when the drug is inhaled 2 h before sBPT.

The role of thromboxane in allergen-induced asthmatic responses

In this study we evaluated the role of thromboxane in causing allergen-induced early and late asthmatic responses and airway hyperresponsiveness in asthmatic subjects. Twelve atopic subjects with stable asthma and documented early and late asthmatic responses to an inhaled allergen were treated with placebo or CGS 13080, a specific thromboxane synthetase inhibitor, given orally (200 mg four times daily) for two days before, the day of, and the day after allergen inhalation. Treatments were administered in a double-blind, placebo-controlled, crossover fashion. The effect of pretreatment with CGS 13080 was examined on serum TxB2 levels and the magnitude of the asthmatic responses after inhaled allergen. Serum TxB2 levels increased significantly from 96 ng.ml-1 (SEM 29) 3 h after diluent to 151 ng.ml-1 (SEM 27) 3 h after allergen (p = 0.008). CGS 13080 pretreatment markedly inhibited the levels of TxB2 at all time points before and after inhaled allergen (p = 0.0001) and had a small but significant effect on the magnitude of the early asthmatic responses after allergen (p = 0.0009). CGS 13080 did not alter either late asthmatic responses, baseline airway responsiveness, or the increase in histamine airway responsiveness after allergen. These results suggest that allergen-induced early asthmatic responses, but not late responses or allergen-induced airway hyperresponsiveness, are partly caused by thromboxane release.

The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man

We have investigated the protective effects of the inhaled cysteinyl leukotriene antagonist, L-648,051, on allergen-induced early asthmatic response (EAR) and late asthmatic response (LAR) and the subsequent changes in bronchial responsiveness to methacholine. Ten atopic men with asthma participated in a double-blind, crossover, placebo-controlled trial. All subjects had documented EAR and LAR to house dust-mite extract. Responsiveness to methacholine was measured the day before and the day after a standardized allergen-challenge test. L-648,051 was inhaled in two doses of 12 mg 20 minutes before and 3 hours after the allergen challenge. The response was obtained from FEV, and flows from maximal (V 40m) and partial (V 40p) expiratory flow-volume curves. All subjects had an EAR and LAR during placebo therapy, but only a minority demonstrated an increase in methacholine responsiveness of more than one doubling dose. The ratio of V 40m to V 40p during methacholine challenge was higher than during both EAR and LAR ( p < 0.05). There was no difference between drug- and placebo-therapy periods in baseline function, EAR, LAR, ratio of V 40m to V 40p, and the allergen-induced hyperresponsiveness ( p > 0.1). These results indicate that an effective aerosolized leukotriene antagonist in man does not protect against allergen-induced airflow obstruction, despite the evidence of an inflammatory response to allergen challenge. This suggests that either the potency or duration of activity of L-648,051 is limited or that leukotrienes C 4 and D 4 do not play a causative role in human allergic asthma.

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 μg), beclomethasone dipropionate (200 μg), 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 < 0.01). The LAR ( p < 0.01) and the allergen-induced increased bronchial responsiveness to histamine 7 hours ( p < 0.07) and 30 hours ( p < 0.05 and p < 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.

A comparison of the protective effect of fenoterol and Sch1000 on allergen-induced asthma

The protective effects of inhaled Sch1000 (80 μg), inhaled fenoterol (800 μg), and placebo on the early asthmatic response induced by inhaled allergen were compared in 10 subjects in a single-blind investigation. Allergen inhalation produced early asthmatic responses in all 10 subjects, with a mean 1-sec forced expiratory volume (FEV 1) fall of 31.1% (range, 23% to 40%). The similarity of the responses to allergen inhalation following no pretreatment and following placebo showed that the allergen-induced response was highly reproducible, with coefficients of variation for the maximum percentage FEV 1 fall of ± 7.2%. Sch1000 produced a slight nonsignificant reduction in the magnitude of the early asthmatic response of 20.7% ± 39.7% ( p > 0.10) for the maximum FEV 1 fall. Fenoterol, however, produced a highly significant reduction in the magnitude of the early of 76.4% ± 23.5% ( p < 0.001) for the maximum FEV 1 fall, which was significantly greater than that produced by Sch1000 ( p < 0.001). These results show that β-adrenergic agonists, such as fenoterol, are more effective than cholinergic antagonists, such as Sch1000, in preventing the early asthmatic response induced by inhaled allergen. Reflex parasympathetic bronchoconstriction is involved to a variable and minor extent in the production of allergen-induced early asthmatic responses.