Site of action of inhaled histamine in asymptomatic asthmatic patients

Histamine inhalation provocation-tests were performed in twenty-two young asthmatics with normal lung-function tests with progressive, increasing doses of a pressurized aerosol of histamine phosphate. Airway resistances (Raw) and N2 washout-curves were recorded. Two different types of response have been observed: (1) in thirteen cases, there was an increase of both flaw and the N2 phase III slope; and (2) in eight cases, there was only an increase in Raw (in one subject there was an increase in the N2 phase III slope only). Comparing the two groups of patients there was no difference in the inhalation procedure, the dose of histamine delivered or the smoking habits and lung-function data, except a slightly higher residual volume/total lung capacity (RV/TLC) ratio in the first group. The histamine-induced changes could not be related to any of the control lung-function data. We conclude that histamine inhalation may induce either peripheral bronchoconstriction only, or central broncho-constriction with or without peripheral bronchoconstriction. A local and/or peripheral vagal-mediated bronchoconstrictor effect could account for the different site of airway response.     

Effect of inhaled indomethacin in asthmatic patients taking high doses of inhaled corticosteroids

Background: Cyclooxygenase products of arachidonic acid may play a part in bronchoconstriction and airway inflammation in asthma. Objective: We sought to determine the effect of inhaled indomethacin on asthma control and asthma exacerbations during reduction of inhaled corticosteroids in patients with moderate-to-severe steroid-dependent asthma. Methods: We conducted a double-blind, randomized, parallel-group, multicenter study in 38 patients with asthma taking high doses (≥1500 μg/d) of beclomethasone dipropionate (BDP). After a run-in period, patients were assigned inhaled indomethacin (50 mg/d) or placebo for 6 weeks, during which the daily doses of BDP were reduced to half at week 2 and then to one third of the baseline dose at week 4. Results: Data were available from 34 patients. After the reduction of BDP doses, FEV₁, peak expiratory flow, asthma symptoms, and exhaled nitric oxide concentrations deteriorated in both treatment groups, but these effects were less pronounced in the indomethacin group compared with the placebo group. During the 6-week treatment period, 89% of the patients receiving placebo had relapse of asthma, whereas only 38% of those receiving inhaled indomethacin did so (P = .003). Conclusion: Inhalation of indomethacin can reduce asthma exacerbations induced by reduction of high-dose inhaled corticosteroid in steroid-dependent asthma. (J Allergy Clin Immunol 2000;105:1134-9.)     

Differences in mouth occlusion pressure and breathing pattern between arm and leg incremental exercise

The aim of the study was to compare breathing pattern, mouth occlusion pressure, mean inspiratory flow and the ratio of mouth occlusion pressure to mean inspiratory flow at the same power output and carbon dioxide output during arm and leg incremental exercise. Mouth occlusion pressure was used as an index of inspiratory neuromuscular activity and its ratio to mean inspiratory flow as an index of the ‘effective’ impedance of the respiratory system. Eight normal subjects performed two incremental exercise tests, one with arms, the other with legs, on different weeks and in randomized order, and on two identical cycle ergometers. The power output was increased by steps of 25 W for arms and 50 W for legs every 4 min until exhaustion. At the same power output, oxygen consumption, carbon dioxide output, ventilation, mean inspiratory flow, mouth occlusion pressure, ‘effective’ impedance (P<0.001) and respiratory frequency (P<0.01) were higher during arm exercise than during leg exercise, whereas inspiratory time (P<0.05) and expiratory time (P<0.01) were lower. At the same carbon dioxide output, mouth occlusion pressure, ventilation, ‘effective’ impedance (P<0.001) and respiratory frequency (P<0.01) were higher and expiratory time (P<0.05) was lower during arm exercise. In conclusion, the higher inspiratory neuromuscular activity and impedance of the respiratory system during arm exercise and the differences observed in ventilation and breathing pattern at equal carbon dioxide output seem related to the differences in exercising muscle afferents and the presence of an increased load due to contraction of rib cage muscles to stabilize posture.     

Repeated histamine inhalation tests in asthmatic patients

Histamine inhalation tests were performed in 12 asthmatic patients using a 2-min tidal breathing inhalation technique. The tests were repeated on separate days with 30-, 60-, and 120-min intervals between inhalation tests. On another day the inhalation tests were repeated four times with 40-min intervals between tests. The geometric mean provocative concentrations of histamine needed to cause a 20% fall in forced expiratory volume in 1 sec (PC₂₀) for the group on the latter study day were 1.67, 1.57, and 1.55 mg/ml (p > 0.25) indicating no change in sensitivity to inhaled histamine with repeated testing. The results suggest that cumulative dose-response curves for drugs potentially affecting the airways or antagonizing histamine can be constructed within 1 day using histamine inhalation tests. The data also suggested that an individual PC₂₀result may be sensitively assessed by comparing it to a ±2 SD range from the mean of a series of control or placebo PC₂₀ values.     

Studies of the effects of inhaled magnesium on airway reactivity to histamine and adenosine monophosphate in asthmatic subjects

Background Magnesium is a cation with smooth muscle relaxant and anti-inflammatory effects and may therefore have a role in the therapy of asthma. Several studies have investigated the effects of intravenous magnesium in acute or stable asthma, but little is known about the effects of inhaled magnesium. Objective To measure the effects of a single inhaled nebulized dose of 180 mg magnesium sulphate on airway reactivity to a direct-acting bronchoconstrictor (histamine) and an indirect-acting bronchoconstrictor (adenosine monophosphate [AMP]) in asthmatic subjects. Objective Two separate randomized, double-blind, placebo-controlled crossover studies, each involving 10 asthmatic subjects. In the histamine study, airway reactivity to histamine was measured and lung function allowed to recover spontaneously over 50 min before administering nebulized magnesium sulphate or saline placebo. Airway reactivity to histamine was then measured at 5 and 50 min. In the AMP study, a single measurement of airway reactivity was made 5 min after magnesium or placebo. Results In the histamine study, the provocative dose required to reduce FEV₁ by 20% (PD₂₀FEV₁) was significantly lower after magnesium than after placebo, by a mean (95% CI) of 1.02 (0.22–1.82) doubling doses at 5 min (P= 0.018), and 1.0 (0.3–1.7) doubling doses at 50 min (P= 0.01). In the AMP study, PD₂₀FEV₁ was also significantly lower at 5 min after magnesium than after saline, by 0.64 (0.12–1.16) doubling doses (P= 0.023), though this difference was not statistically significant after adjustment for differences in baseline FEV₁ on the two study days. Conclusions Inhaled magnesium did not protect against the effects of these direct and indirect bronchoconstrictor stimuli in subjects with asthma, and may have increased airway reactivity to histamine.     

Impact of breathing pattern on work of breathing in healthy subjects and patients with COPD

The impact of the respiratory pattern on respiratory muscle workload represents an unresolved controversy and is important for the treatment of patients with respiratory disorders and respiratory muscle failure. We designed this study to investigate the relationship of respiratory pattern and inspiratory workload. We measured esophageal pressure and inspiratory flow and calculated work of breathing, tidal volume and respiratory rate. Ten healthy subjects and 10 COPD patients participated and performed five different breathing patterns starting from respiratory rate 12 and tidal volume 1l or quiet breathing, respectively. They were instructed to increase respiratory rate by 50 and 100% as well as tidal volume by 50 and 100% while maintaining constant minute-ventilation. In healthy subjects Delta VT was the single best parameter to predict Delta WOB (R=0.958, R(2)=0.918, p<0.0001). The relationships of changes in tidal volume, respiratory rate and rapid shallow breathing index to changes in WOB were linear. In the COPD Delta VT was also the single best parameter to predict changes in work of breathing (R=0.777, R(2)=0.604, p<0.0001), however the relation of respiratory rate and rapid shallow breathing index to work of breathing was exponential (e-function) with lower indices generating higher workload. We conclude that rapid shallow breathing might be a strategy to compensate for burdensome respiratory mechanics. In COPD patients however we observed a critical threshold where any further increases in rapid shallow breathing index will be of no further benefit.     

Plasma histamine changes during provoked bronchospasm in asthmatic patients

Seven patients with bronchial asthma underwent bronchial inhalation challenge with aerosolized allergen extracts and methacholine. Simultaneously, venous blood samples were collected and histamine was measured. Each patient was challenged on successive days with an allergen extract to which he had no skin-sensitizing antibody (skin test-negative allergen), followed by methacholine and skin test-positive allergen. Bronchospasm was not induced by inhalation of skin test-negative allergens but was observed in all patients after methacholine and in the majority of patients after skin test-positive allergens. No changes in plasma histamine were detected after challenges with methacholine and skin test-negative allergens. After challenge with skin test-positive allergens, significant rises in plasma histamine were detected in 5 of 7 patients. Plasma histamine was elevated within the first 5 min after inhalation of aerosolized allergen, and elevations persisted as long as 30 min. These studies showing that histamine increases significantly in the plasma during allergen-induced asthma in man suggest that histamine should be considered as at least one of the mediators of bronchospasm in allergic asthma. Bronchospasm induced by the cholinergic drug methacholine, unlike allergen-induced bronchospasm, is not associated with changes in plasma histamine.     

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)     

Comparison of incremental and bolus dose inhaled allergen challenge in asthmatic patients

BACKGROUND: Attenuation of airway responses to inhaled allergen is increasingly used to evaluate anti-asthma drugs. Many studies use different allergen challenge methods and the presence of the late asthmatic response can be identified by a screening challenge with inhalation of incremental doses of allergen. Once defined, subsequent challenges are often administered as a constant dose based on the dose from the screening challenge. Previously, constant dose challenges have been employed but never validated. OBJECTIVE: A comparative study of two methods of delivering inhaled allergen by evaluating the responses of an incremental dose allergen challenge and the same cumulative dose administered as a bolus over a single inhalation. METHODS: Thirty-five male patients with mild allergic asthma underwent incremental dose challenge followed 3-6 weeks later by a bolus dose challenge. Bronchoconstrictor responses were expressed as the maximum percentage fall in FEV1 from baseline during the early (0-2 h) and late (4-10 h) asthmatic responses and area under the percentage change in FEV1-time curve (AUC). RESULTS: There were no significant differences between the challenges. The mean +/- SEM fall in FEV1 following incremental and bolus dose challenge was 33.1 +/- 1.8% and 29.9 +/- 2.2% during the early response, and 36.9 +/- 2.4% and 34.0 +/- 3.1% during the late response, respectively. The mean +/- SEM AUC following incremental and bolus dose challenge was 35 +/- 3 and 33 +/- 3 Delta%FEV1/h for the AUC0-2 h, 147 +/- 12 and 139 +/- 16 Delta%FEV1/h for the AUC4-10 h, and 204 +/- 14 and 190 +/- 19 Delta%FEV1/h for the AUC0-10 h, respectively. CONCLUSION: Bolus dose allergen challenge is a safe method to administer inhaled allergen in clinical trials with a valid response when compared with incremental dose allergen challenge.     

Effect of combined montelukast and desloratadine on the early asthmatic response to inhaled allergen

BACKGROUND: The early asthmatic response (EAR) to inhaled allergen results from IgE-mediated release of multiple mast-cell mediators, including leukotrienes and histamine, both of which cause bronchoconstriction. Combination therapy directed at blocking the effects of both mediators might protect against the EAR better than either therapy alone. OBJECTIVE: We sought to evaluate the effect of desloratadine and montelukast, administered alone and in combination, on the EAR to inhaled allergen. METHODS: Ten adults with mild-to-moderate atopic asthma participated in a randomized, 4-way crossover study design comparing placebo, 5 mg of desloratadine, 10 mg of montelukast, and the combination administered at 26 hours and 2 hours before each allergen challenge conducted at least 7 days apart. The primary end point was the concentration of allergen that resulted in a 20% decrease in FEV1 (PC20). RESULTS: The geometric mean allergen PC20 (mean log +/- SEM) for combination therapy, montelukast, desloratadine, and placebo was 697 U/mL (2.8433 +/- 0.3253), 338 U/mL (2.5295 +/- 0.2979), 123 U/mL (2.0883 +/- 0.2102), and 104 U/mL (2.0166 +/- 0.2553), respectively (n = 9; P < .00001, ANOVA). Montelukast increased the allergen PC20 4.8-fold, and combination therapy increased the allergen PC20 8.9-fold. The effect of the combination was greater than that with montelukast alone (P < .02). Desloratadine treatment was no different than placebo. CONCLUSIONS: The early response to inhaled allergen was unchanged after desloratadine therapy and partially inhibited with montelukast therapy. The combination of desloratadine and montelukast provided superior efficacy to either blocker administered alone. Investigations into the possible mechanisms of the enhanced inhibition are necessary.     

Ex vivo pharmacologic modulation of basophil histamine release in asthmatic patients

Histamine is one of a range of mediators which play an important role in asthma, and the "releasability" of basophils has been shown to be upregulated in this disease. In vitro , β₂-agonists and to a lesser extent corticosteroids have been shown to reduce histamine release. The ex vivo effects of salmeterol and inhaled corticosteroids on histamine release were studied in 78 asthmatic patients with variable disease severity and 20 control subjects. Spontaneous and anti-IgE-induced histamine release was measured in all subjects. Fifteen patients were not receiving any form of treatment, 42 were treated with inhaled corticosteroids, and 21 received inhaled corticosteroids and salmeterol. Seven patients treated with inhaled corticosteroids and seven patients treated with inhaled corticosteroids and salmeterol were tested twice to assess the effect of salmeterol on histamine release. Nine patients treated with inhaled corticosteroids were tested before and after 1 month of salmeterol treatment to determine the possible inhibition by salmeterol. Patients who were treated with inhaled corticosteroids and salmeterol showed significantly lower levels of spontaneous histamine release (median: 2.5%) than untreated (5.2%) and inhaled corticosteroids-treated asthmatics (3.4%). No tachyphylaxis to salmeterol was observed when patients were tested twice at a 3-month interval. This study suggests that salmeterol may have an additive anti-inflammatory effect with inhaled corticosteroids, although this hypothesis must be tested by further studies involving cells obtained by bronchoalveolar lavage and studies with bronchial biopsies.     

Occlusion pressure and breathing pattern in children with chronic obstructive pulmonary disease

The control of breathing at rest was studied in 30 children (3 to 17 years old) with chronic obstructive pulmonary disease (COPD). Five of them were tested several times during the follow-up of the COPD. Breathing pattern was evaluated and mouth occlusion pressure (PO.1) was measured. Results in COPD children were compared to previously reported values in healthy controls. PO.1 was significantly increased. In 11 children breathing O2, PO.1 decreased but remained at higher levels than predicted. However, the decrease in PO.1 in COPD was not significantly greater than in healthy children. These results may be explained by the relative mild hypoxemia in those children. The increase in PO.1 was significantly correlated with the increase in lung resistance (p less than 0.02) and with the decrease in dynamic lung compliance (p less than 0.01). Most of the COPD children were normocapnic. However, modifications in the breathing pattern were observed. The inspiratory time (TI) was significantly shortened, the expiratory time was prolonged and the TI over the total duration of the respiratory cycle was lowered. The respiratory frequency was unchanged. The tidal volume, normalized for body weight (VTBW), was increased. The mean inspiratory flow (VTBW/TI) was significantly augmented, but not as much as PO.1: in consequence, the effective inspiratory impedance was higher than predicted. Thus, as adults, COPD children had a greater inspiratory neural drive. In contrast to normocapnic COPD adults, they had a modified respiratory timing.     

Breathing pattern and occlusion pressure during moderate and heavy exercise

We studied changes in breathing pattern and mouth occlusion pressure (P0.1) in 11 healthy subjects performing graded steady-state exercise on a cycle ergometer up to the maximal load sustainable for 4 min. With increasing work intensity both the tidal volume (VT) and end-inspiratory volume relations to inspiratory (TI) and expiratory (TE) durations were linear in the moderate work load range; in the high load range VT and end-inspiratory volume tended to plateau with further decreases in TI and TE. The ratio of TI to total breath duration (TI/Ttot) increased with work intensity. Intraindividual coefficients of variation for VT, breathing frequency (f), mean inspiratory flow (VT/TI), and other respiratory variables decreased with increasing work intensity, indicating that breath-to-breath variations in breathing pattern became smaller as the level of ventilation increased. P0.1 rose with VT/TI as a power function with an exponent averaging 1.5 (range 1.3-1.9), indicating that the ratio P0.1/(VT/TI), an index of respiratory system impedance, increased with VT/TI and work intensity. We conclude that in moderate and heavy exercise the work of inspiration at a given ventilation is reduced because of the increase in TI/Ttot, the impedance of the respiratory system increases with work intensity because of both an increase in f and a flow-dependent rise in airway resistance, and the neuromuscular inspiratory activity is reflexly augmented because of internal flow-resistive loading.     

Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids

Nedocromil sodium is a non-steroidal prophylactic agent developed for the management of asthma. We have assessed the steroid sparing potential of inhaled nedocromil sodium 4 mg four limes daily in a randomized, double blind, placebo controlled study in 69 asthmatic subjects controlled on inhaled beclomethasone dipropionate in the dose range 1000 2000 μg daily. Following a 4 week run-in period subjects added nedocromil sodium or placebo by metered dose inhaler to their usual medication for a further 4 weeks. The dose of inhaled steroid was then reduced at fortnightly intervals according to a predetermined schedule, with monitoring of asthma severity, symptom scores, bronchodilator use and peak flow recordings. Sixty subjects entered the steroid reduction phase and achieved median (range) % decreases in steroid dose of 80 (17-100)% with nedocromil sodium compared to 65 (0-100)% with placebo (P = 0.34) with 14 patients in the nedocromil sodium group and 10 in the placebo group being withdrawn completely from inhaled steroids. Subjective global assessment scores were significantly better with nedocromil sodium (mean 2.14) than with placebo (2.93; P<0.02) though there was no difference between individual daily symptom scores. In this study therefore in asthmatic patients controlled on high doses of inhaled steroids, nedocromil sodium was well tolerated but the smalt differences in steroid sparing effect between nedocromil and placebo were not statistically significant.     

The influence of Cimetidine and Ranitidine on basophil histamine release and bronchial reactivity in asthmatic patients

Anti-IgE induced histamine release from isolated basophils after Cimetidine and Ranitidine administration was evaluated in 22 patients with atopic bronchial asthma.The histamine provocation test after Ranitidine treatment in 10 patients with atopic bronchial asthma and 10 patients with peptic ulcer was also performed.Investigationsin vitro revealed that Cimetidine and Ranitidine in low concentrations had an inhibitory effect whereas in concentrations of over 10^–6 M and 10^–4 M, respectively, they enhanced histamine release.Investigationsin vivo after administration of Ranitidine showed that it does not cause marked changes in the bronchial reactivity in patients with bronchial asthma and any change in patients with peptic ulcer.These preliminary studies seem to suggest that in patients with atopic bronchial asthma and concomitant peptic ulcer Ranitidine is preferable to Cimetidine in the treatment of digestive tract disorders.This work was supported by the Polish Academy of Science (grant Nr 06.03).