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ABSTRACT: 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.
European Respiratory Journal 02/2009; 33(6):1302-8. · 5.89 Impact Factor
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ABSTRACT: 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.
Allergy 02/2005; 60(1):56-9. · 6.27 Impact Factor
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ABSTRACT: Determinants of changes in airway caliber after allergen challenge include nonallergic airway responsiveness, immune response and dose of allergen given. However, determinants of the airway inflammatory response to allergens remain to be determined.
To assess the relationship between skin reactivity to airborne allergens and lower airway eosinophilic response to allergen exposure in asthma and allergic rhinitis.
Forty-two subjects with mild allergic asthma (mean age 24 years) and 14 nonasthmatic subjects with allergic rhinitis (mean age 25 years) had allergen skin prick tests and titration with the allergen chosen for subsequent challenge. On a second visit, 31 asthmatic subjects had a conventional challenge while 11 asthmatic subjects and all rhinitic subjects had a low-dose allergen challenge over four subsequent days. Induced sputum samples were obtained at 6 and 24 h after the conventional challenge and at days 2 and 4 of the low-dose challenge.
In the asthmatic group, there was a weak correlation between wheal diameter induced by the concentration used for challenge and increase in eosinophils 6 h postconventional challenge (r = 0.372, P = 0.05), but no correlation was observed following the low-dose challenge. Rhinitic subjects showed a correlation between wheal diameter with the allergen dose used for bronchoprovocation and increase in eosinophils at day 2 of low dose (r = 0.608, P = 0.02).
This study suggests that immediate immune responsiveness to allergen, assessed by the magnitude of the skin response, is a significant determinant of allergen-induced airway eosinophilia and can help to predict the airway inflammatory response.
Allergy 10/2003; 58(9):945-9. · 6.27 Impact Factor
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ABSTRACT: Viral respiratory infections in infancy may contribute to the development of airway hyper-responsiveness (AHR) in childhood but their effects on respiratory function at the adult age are still uncertain. A group of 42 subjects aged 17-35 with a pediatrician-made diagnosis of severe bronchiolitis in infancy (Br) were compared for the presence of asthma and AHR to a control group (C) paired for age and gender, without evidence of lower respiratory disease in infancy. All had a respiratory and environmental questionnaire, allergy skin prick tests, blood eosinophil count, total serum IgE determination and measurements of expiratory flows and airway response to methacholine. In Br and C groups, respectively, 38 and 12% of subjects had a physician-made diagnosis of asthma, 26 and 7% used bronchodilators and 12 and 0% an inhaled corticosteroid; 71 and 67%, respectively, were atopic, 50 and 24% were smokers and 43 and 17% had a first-degree relative with asthma. Mean baseline FEV1 and FEV1/FVC ratio were lower in the Br than in the C group, with 94/103% (P=0.002) and 80/87 (P<0.0001) of the predicted value, respectively. Geometric mean PC20 methacholine was significantly lower in the Br than in the C group 3.9/20.3 mg ml(-1) (P<0.0001). Mean blood eosinophil count and serum IgE levels were similar in both groups (P> 0.05). In conclusion, asthma and AHR were found more frequently in young adults with a past history of bronchiolitis, suggesting that this type of respiratory infection may contribute to altered pulmonary function in adulthood, although it may also represent an early manifestation of asthma. The influence of potential confounding factors, such as familial predisposition and exposure to cigarette smoke on the development of asthma and AHR in the Br group, cannot be excluded.
Respiratory Medicine 04/2000; 94(3):288-94. · 2.47 Impact Factor
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ABSTRACT: Intravenous administration of a humanized monoclonal antibody of IgE (E25) attenuates the early and late phase response to inhaled allergen in allergic asthmatic subjects. To test whether direct delivery of E25 to the airway might have the same effect, we conducted a randomized, double-blind, three group study in 33 subjects with mild allergic asthma (20 to 46 yr of age, 21 men, FEV(1) > 70% predicted). The airway responses to aerosolized allergen were determined at baseline, after 2 and 8 wk of once daily treatment with aerosolized placebo (n = 11), aerosolized E25 1 mg (n = 12), or aerosolized E25 10 mg (n = 10), and after 4 wk of treatment withdrawal. We found that E25 was detectable in the serum during aerosol treatment, although serum IgE did not change significantly in any of the three groups during treatment. In addition, both doses of E25 were no more effective than placebo in attenuating the early phase responses to allergen at both times during treatment. Although aerosolized E25 was generally well tolerated, one subject receiving aerosolized E25 10 mg daily was found to have serum IgG and IgA antibodies to E25. We conclude that aerosol administration of an anti-IgE monoclonal antibody does not inhibit the airway responses to inhaled allergen in allergic asthmatic subjects. We speculate that the observed lack of efficacy may be due to the inability of aerosol route of delivery to result in high enough concentrations of E25 in the tissue compartments surrounding IgE effector cells to neutralize IgE arising from local airway and pulmonary sources and IgE arising from the vascular space. Additionally, the aerosol route of delivery of monoclonal antibodies may be more immunogenic than the parenteral route.
American Journal of Respiratory and Critical Care Medicine 10/1999; 160(3):1023-7. · 11.08 Impact Factor
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ABSTRACT: Changes in lung volumes may contribute to the perception of bronchoconstriction-induced breathlessness.
To verify whether histamine-induced increases in lung volumes are more marked in asthmatic subjects with normal compared with low symptom perception scores and whether changes in lung volumes are detected similarly in both groups of subjects.
A group of 16 asthmatic subjects with low (< or =1) breathlessness score (scale: 0 to 10) at 20% fall in FEV1 (PS20B) on at least one of 2 histamine inhalation tests (HIT) performed on separate days (hypoperceivers) were studied. They were compared with a group of 12 asthmatic patients with a PS20B >1 on the 2 tests (normoperceivers). Lung volumes were measured before and after the second HIT and changes correlated with PS20B and PS20 for the sensation of chest tightness PS20CT) and with the slopes of these perception scores/% fall in FEV1 (PS B or CT/deltaFEV1).
Hypoperceivers had a mean (+/-sem) PS20B of 1.03+/-0.20 on HIT1 and 0.66+/-0.12 on HIT2 (P>.05) and normoperceivers 2.59+/-0.14 on HIT1 and 2.38+/-0.18 on HIT2 (P>.05). Subjects' age, gender, duration of asthma, medication needs, and baseline and post-HIT pulmonary function (FEV1, FVC, FRC) were not significantly different between the two groups. Contrary to PS20B (P<.0001), PS20 for chest tightness (PS20CT) was similar in the two groups (HIT 1/2; hypoperceivers: 1.41/1.07, normoperceivers: 1.57/1.99, both P>.05). Perception of bronchoconstriction-induced breathlessness was not correlated with the degree of reduction in FVC at 20% fall in FEV1. In normoperceivers, (PS B/deltaFEV1) was significantly correlated with the postchallenge increase in FRC (rs = 0.63, P=.036) although there was no significant correlation in hypoperceivers (rs = -0.041, P>.05).
Changes in lung volumes were similar in hypoperceivers and hyperperceivers of bronchoconstriction. Perception of breathlessness, however, was positively correlated with changes in lung volumes in normoperceivers but not in hypoperceivers suggesting that normoperceivers have an ability to detect these changes, presumably through proprioception, ability that is lacking or lost in hypoperceivers. More subjects should be studied to confirm this finding.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 10/1998; 81(4):315-21. · 2.83 Impact Factor
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J C Kidney,
L P Boulet,
F E Hargreave, F Deschesnes,
V A Swystun,
P M O'Byrne,
N Choudry,
M M Morris,
B Jennings,
N Andersson,
A Andreasson,
D W Cockcroft
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ABSTRACT: Inhaled corticosteroids are the most commonly used antiinflammatory agents for asthma. There is no simple way to compare objectively the relative potency of inhaled corticosteroids. The allergen-induced late asthmatic response (LAR) can be suppressed by a single dose of inhaled corticosteroid.
This study was undertaken to evaluate LAR as a model for the determination of the relative potency of single doses of inhaled corticosteroids.
We compared doses of 200 and 800 microg of a highly active inhaled corticosteroid (budesonide) with placebo and a marginally active investigational inhaled corticosteroid (D5159). Ten atopic patients with asthma completed a randomized, double-blind, double-dummy, multicenter, four-way, crossover trial. A standardized allergen challenge with the identical dose of allergen was performed 10 minutes after each of four blinded, single-dose treatments: 200 microg of budesonide, 800 microg of budesonide, 8 mg of D5159, and placebo, all administered from Turbuhaler. The LAR was recorded as the maximum percent fall in FEV1 between 4 and 7 hours, and the allergen-induced increase in methacholine airway responsiveness at 24 hours was recorded as the A log PC20 from the day before to the day after allergen challenge.
There were no significant differences in the early asthmatic responses during the 4 days; the mean maximum percent in FEV1 fall ranged between 19.5% and 22%. D5159 produced a slight inhibition of the LAR with maximum percent fall in FEV1 recorded as 28.8% +/- 5.0% for D5159 versus 34.1% +/- 4.8% for placebo (p < 0.05). There was a greater reduction recorded after administration of the two doses of budesonide. The mean LAR was 15.1% +/- 3.8% for 200 microg of budesonide and 11.2% +/- 2.3% for 800 microg of budesonide (p < 0.01 compared with placebo and D5159). The two doses of budesonide were not statistically different. Airway responsiveness to methacholine increased by 1.07 doubling doses 24 hours after allergen challenge. This increased airway responsiveness was slightly, but not significantly, reduced by the three active treatments (0.6 to 0.91 doubling doses).
The allergen-induced LAR model was able to differentiate a single dose of an active inhaled corticosteroid from placebo and a highly potent inhaled corticosteroid from a weak inhaled corticosteroid. The model did not differentiate between 2 fourfold doses of the highly active inhaled corticosteroid (at the doses used in this study), neither for the fall in FEV1 nor for the increase in airway hyperresponsiveness.
Journal of Allergy and Clinical Immunology 07/1997; 100(1):65-70. · 11.00 Impact Factor
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L P Boulet,
K R Chapman,
J Côté,
S Kalra,
R Bhagat,
V A Swystun,
M Laviolette,
L D Cleland, F Deschesnes,
J Q Su,
A DeVault,
R B Fick,
D W Cockcroft
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ABSTRACT: Inhaled allergens, acting through IgE-dependent mechanisms, are important triggers of asthma symptoms and inducers of airway hyperresponsiveness and airway inflammation. The effect of anti-IgE recombinant humanized monoclonal antibody-E25 (rhuMAb-E25) on the provocation concentration of allergen causing a 15% fall in FEV1 (allergen PC15) during the allergen-induced early asthmatic response (EAR) was assessed in a multicenter, randomized, double-blind, parallel group study. Ten of 11 allergic asthmatic subjects randomized to receive intravenous rhuMAb-E25, 2 mg/kg on study day 0 and 1 mg/kg on Days 7, 14, 28, 42, 56, and 70 completed the study; nine received intravenous placebo. The allergen PC15 was measured on Days -1, 27, 55, and 77 and methacholine PC20 on Days -2, 42, and 76. rhuMAb-25 was well tolerated and only one patient (active group) was withdrawn because of a generalized urticarial rash after the first dose. Compared with baseline values (Day -1), the median allergen PC15 on Days 27, 55, and 77 were increased by 2.3, 2.2, and 2.7 doubling doses (delta log PC15/0.3) respectively with rhuMAb-E25 and -0.3, +0.1, and -0.8 doubling doses with placebo (p < or = 0.002). Methacholine PC20 improved slightly after rhuMAb-E25, this change becoming statistically significant on Day 76 (p < 0.05); no change was observed in the placebo group. Mean serum-free IgE fell by 89% after rhuMAb-E25 while there was no significant change after placebo. The inhibitory effects of rhuMAb-E25 on allergen-induced EAR suggest that it may be an effective, novel antiallergic treatment for asthma.
American Journal of Respiratory and Critical Care Medicine 06/1997; 155(6):1835-40. · 11.08 Impact Factor
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ABSTRACT: We compared the effects of an allergen challenge on airway responsiveness to methacholine, the slope of the dose-response curve (DRC) and post-methacholine fall in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1)/FVC, and determined whether any changes in these parameters were related to the presence and magnitude of the late asthmatic response (LAR) in mild stable asthma. Twenty-three allergic asthmatic subjects had an allergen challenge, preceded and followed 24 (n = 12) and/or 48 (n = 22) h later by a methacholine challenge. Sixteen subjects had a dual asthmatic response to the allergen. On the post-allergen methacholine challenge, as compared with the pre-allergen test, differences in mean fall in FVC or FEV1/FVC at 20% fall in FEV1 and the slope of the DRC did not achieve statistical significance, even in the group with LAR, which showed a significant increase in airway responsiveness at 24 h. There was, however, a correlation between allergen-induced changes in PC20 and (1) the change in post-methacholine FVC fall in the LAR group at 48 h, and (2) the change in the slope of the DRC in the early-asthmatic-response group at 24 h. In conclusion, allergen-challenge-induced changes in airway response to methacholine are heterogeneous among asthmatic subjects and although it may increase airway responsiveness (PC20), particularly in late responders, it minimally affects the other aspects of airway response to methacholine, suggesting that a more powerful or sustained allergic stimulus is required to modify the latter.
International Archives of Allergy and Immunology 09/1996; 110(4):388-96. · 2.40 Impact Factor
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ABSTRACT: Perception of bronchoconstriction varies between individuals and its determinants remain to be identified. The perception of airflow obstruction and breathlessness during induced bronchoconstriction was studied, and the effects of anxiety, repetition of the stimulus, and bronchodilator needs on these measurements were examined in normal and asthmatic subjects.
Fifteen normal (control) and 25 asthmatic subjects had two consecutive methacholine inhalation tests to induce a 20-50% fall in FEV1. Evaluation of the perceived magnitude of airflow obstruction, breathlessness, level of anxiety generated, and bronchodilator needs was obtained before each FEV1 measurement on a modified Borg scale from 0 to 10.
Mean (SE) maximal fall in FEV1 in asthmatic and control subjects was of similar magnitude: test 1, 37.6 (1.4)% and 38.7 (3.1)%, and test 2, 36.0 (1.6)% and 27.7 (2.4)% respectively. There was a large interindividual variation in perception of airflow obstruction and breathlessness but, although they were well correlated in asthmatic subjects, they were perceived differently by the control subjects. Perception of airflow obstruction was greater in asthmatic subjects. The level of anxiety and the bronchodilator use were low and did not influence perception.
During induced bronchoconstriction, the overall perception of airflow obstruction and breathlessness were similar among asthmatic subjects but controls showed a higher perception of airflow obstruction for any given level of breathlessness. Asthmatic subjects perceived airflow obstruction and breathlessness to a greater degree than did controls but anxiety and bronchodilator need were not correlated with respiratory sensation. The variability of bronchodilator use for similar degrees of bronchoconstriction suggests that it may be misleading to assess the severity of asthma control using only this indirect measure.
Thorax 11/1994; 49(10):965-70. · 6.84 Impact Factor
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ABSTRACT: Using a mixed within-between design, this study was designed to evaluate the sensorial and cognitive/evaluative aspects of bronchoconstriction induced by progressive methacholine inhalation. 25 asthmatic patients and 15 normal controls were given two consecutive bronchoconstriction tests, inducing a fall of > 30% of the forced expiratory volume in 1 sec (FEV1), which was measured after each inhalation of methacholine. Immediately before each FEV1 measurement, Ss rated perceived bronchial closing, discomfort of breathing and anxiety, as well as the need to use a bronchodilator. In addition to state-anxiety, after each bronchoconstriction test asthma symptoms were evaluated by means of a Free Symptom Report and the Asthma Symptom Checklist. The results show that during the first test, asthmatic patients perceived their symptoms more accurately than non-asthmatic controls. However, during the second test, asthmatic patients became less accurate, while normal controls increased their accuracy of symptom report. These changes were not parallelled for the Free Symptom Report or the Asthma Symptom Checklist. These results suggest that, depending on situational circumstances, patients rely on their cognitive schemata to report asthma symptoms. Need for bronchodilator use was related to perceived discomfort but not to actual or perceived bronchial closing. Clinical implications of this study are discussed.
Behaviour Research and Therapy 07/1994; 32(6):623-8. · 3.30 Impact Factor
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ABSTRACT: We studied 19 subjects with asthma (11 men and eight women, aged 20 to 66 years), 6 months to 5 years after a near-fatal (NF) episode of asthma (NF group). Mean duration of asthma was 16.3 +/- 2.4 years. On reevaluation, all subjects were using an inhaled beta 2-agonist and inhaled steroids (mean daily dose of budesonide, 1070 micrograms [N = 5], and beclomethasone, 1079 micrograms [N = 14]). Two subjects were taking prednisone, 10 and 15 mg/day. Subjects were matched for age, sex, atopic status, baseline FEV1, and medication use to a control group (C group) of subjects with asthma who had never experienced an NF asthma episode. All subjects had the following evaluation: (1) questionnaire on the characteristics of their asthma, (2) spirometry, (3) morning and evening measurements of peak expiratory flow rates (PEFR) with daily recordings of asthma symptoms for 4 weeks, and (4) psychometric evaluation with the Minnesota Multiphasic Personality Inventory. Ten subjects of the NF group and 13 of the C group had a methacholine challenge with scoring of dyspnea on a modified Borg scale. Mean percent predicted (+/- SEM), FEV1, FVC, and PEFR were similar for the NF and C groups with respective values of 63.4 (4.4), 61.3 (5.6), 81.1 (4.5), 79.1 (3.8), 61.3 (5.6), and 62.4 (6.1). Geometric mean of the provocative concentration of methacholine causing a 20% drop in FEV1 (milligrams per milliliter) was 0.61 for the NF group (N = 10) and 1.18 for the C group (N = 13).(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Allergy and Clinical Immunology 01/1992; 88(6):838-46. · 11.00 Impact Factor
