We defined the contribution of histamine and leukotrienes to allergen-induced airway obstruction in asthmatics; 12 subjects with allergic asthma underwent identical allergen bronchoprovocations on four occasions. At a control session, all subjects displayed early (EAR) and late asthmatic (LAR) reactions. The mean (+/- SE) drop in FEV1 during EAR (0-2 h) and LAR (2-12 h) was 29 +/- 2% and 28 +/- 4%, respectively. Thereafter, the influence of 1 wk randomized pretreatment with the leukotriene receptor antagonist zafirlukast (Accolate) (80 mg twice daily), the antihistamine loratadine (10 mg twice daily), and the combination of both antagonists was assessed. Expressed as AUC FEV1 in percent of the control reaction, zafirlukast reduced the response during EAR and LAR by 62 +/- 11% and 55 +/- 12%, respectively (p < 0.05 versus control). Loratadine inhibited EAR and LAR by 25 +/- 14% and 40 +/- 16%, respectively (p < 0.05 versus control). Zafirlukast was significantly more effective than loratadine during EAR but not during LAR. The combination of zafirlukast and loratadine reduced the AUC FEV1 during EAR and LAR further, by 75 +/- 8% and 74 +/- 14%, respectively (p < 0.05 versus control). The combination was significantly (p < 0.05) more effective than either drug alone during the LAR. The findings indicate that leukotrienes and histamine together mediate the major part of both the EAR and the LAR following exposure of asthmatics to allergen. Combination of leukotriene antagonism and antihistamines may represent a new strategy for treatment of airway obstruction in asthma.
The development of bronchial hyperresponsiveness (BHR) in asthma is considered to be caused by inflammation of the airway. In IgE-mediated allergy BHR is related to the occurrence of late phase reactions. We have previously shown that exposure to low doses of allergen can cause isolated late reactions. These findings are potentially of clinical importance, since exposure to low, subclinical allergen doses may lead to bronchial inflammation and increasing bronchial responsiveness without necessarily causing immediate bronchoconstriction. This study was performed to investigate whether repeated exposure to low doses of allergen could induce a change in BHR. The trial comprised two groups of five and eight patients with a history of allergic asthma. They were submitted to a series of allergen inhalations for 5-7 days. They were given the same low allergen dose (1-10 biological units) each day. Before and after the allergen exposure period histamine challenges were performed. After the week of allergen inhalation the bronchial responsiveness was increased in 11 of 13 patients.
Increased levels of exhaled carbon monoxide (fractional concentration of CO in expired gas (FE,CO)), measured with an electrochemical sensor, have been reported in patients with inflammatory airway disorders, such as asthma, rhinitis and cystic fibrosis. This study aimed to evaluate these findings by using a fast-response nondisperse infrared (NDIR) analyser, and to compare these measurements with the fractional concentration of nitric oxide in exhaled air (FE,NO). Thirty-two steroid-naïve asthmatics, 24 steroid-treated asthmatics (16 patients with allergic rhinitis, nine patients with cystic fibrosis), and 30 nonsmoking healthy controls were included. CO measurements with the NDIR analyser were performed simultaneously with nitric oxide (NO) analysis (chemiluminescence technique). After 15 s of breath-hold, single-breath exhalations over 10 s were performed at two flow rates and end-tidal plateau concentrations were registered. An electrochemical CO sensor was used independently with an exhalation to residual volume, after a 15 s breath-hold. None of the two CO analysers gave a significant increase in FE,CO in the groups of patients with inflammatory airway disorders compared to controls. FE,NO was significantly elevated in steroid-naïve asthmatics and subjects with allergic rhinitis, but not in steroid-treated asthmatics and subjects with cystic fibrosis. Reducing exhalation flow rate by 50% gave a two-fold increase in FE,NO, while FE,CO was unaffected. A significant increase was seen in FE.CO, but not in FE,NO, when comparing with and without a 10 s breath-hold. In conclusion, the fractional concentration of carbon monoxide in expired gas was not increased in any of the patient groups, while the fractional concentration of nitric oxide in expired gas was significantly elevated in patients with steroid-naïve asthma and allergic rhinitis. Moreover, carbon monoxide was unaffected by flow rate but increased with breath-hold, suggesting an origin in the alveoli rather than the conducting airways.
Summary Late allergic inflammatory reactions are probably of major importance for the development of asthma. In order to study the occurrence of early and late asthmatic reactions after challenge with different doses of allergen, inhalation provocation tests were performed in 13 patients with mild or moderate symptoms of allergic asthma. The provocation series was started with a low allergen dose (0.1–10 BU), which was then increased in successive ten‐fold increments at intervals of 1 week until a pronounced bronchial reaction developed. Three different reaction patterns were observed. Six patients showed an isolated late reaction to relatively low doses of allergen. In four patients an immediate reaction was followed by a late reaction—a so‐called dual response, and in three patients only an immediate reaction occurred. In four of the six patients who showed only a late reaction a higher allergen dose was given and this resulted in dual reactions in all four. One patient was challenged with an even higher dose, to which she reacted with an immediate response alone. After a late reaction, bronchial variability with low PEF values was observed over a period of several days. It is thus possible for an isolated late asthmatic reaction to be provoked by a low dose of inhaled allergen. This can be of clinical importance, repeated small doses of allergen may be unnoticed but still give bronchial inflammation and asthmatic symptoms.
Repeated low-dose allergen inhalation challenge mimics natural allergen exposure, providing a model for early mechanisms in the triggering of asthma. The current authors performed a controlled study to evaluate the time course of changes in exhaled nitric oxide fraction (Fe,NO) and urinary biomarkers of airway inflammation.Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods, with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and Fe,NO and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine.Despite no change in pulmonary function (forced expiratory volume in one second mean¡SEM fall 0.3¡0.7 versus 0.6¡1.0%, for diluent and allergen, respectively) and no asthma symptoms, repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in Fe,NO (up to a doubling from baseline) and a small increase in the mast cell marker 9a11b-prostaglandin F 2 after adenosine challenge.In conclusion, serial measurements of exhaled nitric oxide fraction have the potential to provide a very sensitive strategy for early detection of emerging airway inflammation and subsequent changes in airway hyperresponsiveness to histamine.
Abstractof leukotrienes. Among such antileukotriene drugs, specific receptor antagonists of the Background -Leukotriene receptor antagonists significantly blunt allergen-in-cysteinyl leukotrienes (LTC 4 , LTD 4 and LTE 4 ) have been found to inhibit asthmatic reacduced bronchoconstriction in asthmatic subjects. Inhibitors of leukotriene syn-tions induced by allergens, 3-6 exercise, 7-9 and aspirin. 13 which has a pivotal role in the stimulation-evoked synthesis of leukotrienes asthma and bronchial hyperresponsiveness to histamine were recruited. On two from arachidonic acid. Consistent with this mode of action, BAYx 1005 has been found to different occasions each subject inhaled a single dose of allergen, previously de-inhibit IgE-dependent leukotriene formation in human lung in vitro, as well as the allergentermined to cause at least a 20% fall in forced expiratory volume in one second induced reactions in isolated human bronchi and animal models of asthma. 14-16(FEV 1 ) four hours after ingestion of 750 mg BAYx 1005 or placebo in a double blind This study evaluates the effect of BAYx 1005 on allergen-induced bronchoconstriction in a crossover design. Urinary excretion of leukotriene E 4 was measured before and group of atopic asthmatic subjects. Furthermore, allergen provocation of asthmatic during the challenges. Results -The mean (SE) maximal fall in subjects is associated with release of LTE 4 into the urine 17-20 because a significant proportion FEV 1 was 7.1 (1.7)% after BAYx 1005 and 21.0 (3.0)% after placebo (p<0.001). The of cysteinyl leukotrienes formed in the lungs is excreted by this route, 21 22 so the effect mean difference between treatments was 13.9 (95% CI 7.0 to 20.8) for the maximal of BAYx 1005 on endogenous formation of leukotrienes was assessed by serial measfall in FEV 1 . All subjects were protected by BAYx 1005, the mean inhibition of the urements of urinary levels of LTE 4 .Despite the current development of antifall in FEV 1 being 70.0 (7.0)%. The mean area under the curve (AUC) for urinary leukotriene drugs for clinical treatment of asthma, a limited number of studies have been excretion of leukotriene E 4 in the first two hours after the challenge was 1.7 (0.9) after published on the effects of different anti-
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