Bronchial hyperreactivity to histamine in aspirin sensitive asthmatics: relationship to aspirin threshold and effect of aspirin desensitisation.

Twenty seven aspirin sensitive asthmatic patients were studied to determine the relationship between non-specific bronchial responsiveness to inhaled histamine and the degree of sensitivity to aspirin (aspirin threshold dose). No correlation was found between provocative concentration of histamine (PC20H) and aspirin threshold dose. In 11 patients the influence of aspirin desensitisation on bronchial reactivity to inhaled histamine was examined. Mean PC20H measured the day after the patients were desensitised to 600 mg of aspirin did not change significantly from the values before desensitisation. These observations suggest that sensitivity to aspirin and non-specific bronchial hyperreactivity in asthmatic patients are independent phenomena.     

Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon. CONCLUSIONS--The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.     

Effect of pH on bronchial response to inhaled histamine.

In order to investigate the effect of pH on bronchial responsiveness to inhaled histamine, 15 subjects with non-specific bronchial hyperreactivity performed two histamine inhalation tests, one with unbuffered, and the other with buffered histamine acid phosphate solutions. The unbuffered histamine solutions were prepared with 0.9% sterile saline and had a pH range from 4.3 to 7.3, while the buffered histamine solutions were prepared with a phosphate buffer and had a pH range of 6.5 to 7.4. The two histamine inhalation tests were similar in all other regards. The geometric mean histamine provocation concentration required to produce a 20% reduction in FEV1 (PC20) was significantly lower for the unbuffered histamine (1.33 mg/ml) than for the buffered histamine (1.67 mg/ml), p less than 0.05. The two PC20s differed by less than one doubling dilution, the range of reproducibility of the test, in 12 of the 15 subjects. The pH effect was only noted when the pH of the histamine solutions was below five (histamine concentrations from one to eight mg/ml). We conclude that the acid pH of higher concentrations of histamine acid phosphate solutions has a slight but significant enhancing effect on the bronchial responsiveness to inhaled histamine.     

Regular inhaled beta agonist in asthma: effects on exacerbations and lung function.

BACKGROUND: A comparison of the effects of regular upsilon as needed inhaled beta agonist treatment on the control of asthma in the last 16 weeks of each of two 24 week treatment periods has been reported. This paper presents additional information on exacerbations of asthma and trends in lung function, airways hyperresponsiveness to methacholine, and bronchodilator responsiveness during the entire 24 week periods of regular or as needed beta agonist treatment. METHODS: Subjects undertook a year long randomised, double blind crossover study of regular upsilon as needed inhaled beta agonist treatment. Fenoterol (400 micrograms) or matching placebo was inhaled as a dry powder four times daily for 24 weeks, then subjects crossed over to the alternative regimen. Treatment with inhaled corticosteroids was used by 50 of the 64 subjects in constant doses throughout the study. Symptoms, peak expiratory flow rates, and drug use were recorded daily, spirometry was performed every four weeks, and methacholine and bronchodilator responsiveness were measured every eight weeks. RESULTS: Exacerbations of asthma symptoms occurred earlier and more often during regular treatment with fenoterol and four of five severe exacerbations requiring admission to hospital occurred during the period of regular treatment. Prebronchodilator forced expiratory volume in one second (FEV1) was on average 0.15 litres lower (95% confidence interval (95% CI) 0.11-0.19) and vital capacity (VC) 0.12 litres lower (95% CI 0.08-0.16) than during the placebo period. Morning peak flow rates were significantly lower and evening peak flow rates significantly higher, with an increase in diurnal variation from 9.8% (95% CI 6.9-12.8) to 17.5% (95% CI 13.8-21.3) during regular treatment. Geometric mean concentration of methacholine causing a 20% fall in FEV1 from the value after saline (PC20) decreased significantly from 1.63 to 1.15 mg/ml, indicating increased bronchial hyperresponsiveness during regular treatment. Response to bronchodilator, as measured by the % increase in postbronchodilator FEV1 related to prebronchodilator FEV1, was maintained with no evidence for tachyphylaxis. CONCLUSION: Chronic use of inhaled fenoterol resulted in more exacerbations, a significant decline in baseline lung function, and an increase in airway responsiveness to methacholine in asthmatic subjects, but did not alter bronchodilator responsiveness. These findings support the previous report that regular inhaled beta agonist treatment is deleterious in the long term control of asthma.     

Decrease of histamine induced bronchoconstriction by caffeine in mild asthma.

BACKGROUND--While high doses of caffeine may affect pulmonary function and bronchial challenge tests in patients with mild asthma, the effects of lower doses (< or = 5 mg/kg) are less well documented. Specific recommendations exist for withholding theophylline, but not caffeine, before bronchoprovocation and pulmonary function testing. METHODS--To assess the effect of a single oral dose of caffeine (5 mg/kg) on FEV1 and bronchial responsiveness to histamine a double blind, placebo controlled study was performed in eight patients with mild stable asthma. RESULTS--While caffeine had no effect on FEV1, mean (95% confidence interval) log PC20 histamine was significantly higher 150 minutes [caffeine = 0.99 (0.2) mg/ml, placebo = 0.53 (0.29)] and 240 minutes [caffeine = 0.89 (0.24), placebo = 0.44 (0.26)] after administration of caffeine than after placebo. CONCLUSIONS--Caffeine should be excluded from the diet for a period of more than four hours before bronchial provocation testing. The exact length of time for which it must be excluded requires further study.     

Effect of an oral gold compound, auranofin, on non-specific bronchial hyperresponsiveness in mild asthma.

BACKGROUND--A recent double blind clinical trial in Japan has shown that auranofin (6 mg/day) is a useful treatment for patients with moderate to severe asthma. To investigate the mechanism of action of auranofin the bronchial responsiveness to inhaled methacholine has been studied in well controlled asthmatic subjects. METHODS--Nineteen adult asymptomatic asthmatic subjects received auranofin (3 mg orally twice a day) or inactive placebo in random order for 12 weeks in a double blind fashion. Bronchial responsiveness to inhaled methacholine and pulmonary function tests were measured at the same time on different days before, and six and 12 weeks after, each treatment. RESULTS--Non-specific bronchial hyperresponsiveness 12 weeks after treatment with auranofin was decreased compared with that before treatment with auranofin and 12 weeks after treatment with inactive placebo, although the treatment did not improve pulmonary function tests. CONCLUSIONS--Non-specific bronchial hyperresponsiveness 12 weeks after treatment with auranofin is decreased in a group of mild asymptomatic asthmatic patients with normal lung function.     

Effect of caffeine on histamine bronchoprovocation in asthma.

It was recently reported that caffeine may reduce the clinical symptoms of asthma and may prevent the clinical manifestations of this disease. The effect of caffeine on histamine responsiveness is unknown. The effect of caffeine (5 mg/kg) and placebo on histamine responsiveness (the provocation concentration causing a 20% fall in FEV1, PC20) was studied in 10 subjects with mild asthma (prechallenge FEV1 84% of predicted value). The PC20 for histamine bronchoprovocation after caffeine ingestion was 2.65 (95% confidence limits 0.99, 7.10) mg/ml. After placebo the PC20 was 1.89 (0.96, 3.71) mg/ml. It is concluded that caffeine in a dose equivalent to about three cups of coffee has a very small effect, if any, on histamine bronchoprovocation in those with mild asthma. Specific instructions about not having drinks containing caffeine before histamine challenge are therefore not necessary.     

Inhaled antihistamines--bronchodilatation and effects on histamine- and methacholine-induced bronchoconstriction.

To assess further the bronchodilator activity of inhaled antihistamines ten stable asthmatic subjects inhaled aerosols of clemastine, 1 mg/ml, and saline placebo administered double blind. Subjects underwent bronchial challenge with increasing concentrations of histamine and methacholine, and specific airways conductance was measured by whole body plethysmography at each concentration. There was a significant 21.9% increase in specific airways conductance after inhalation of clemastine. Subjects could tolerate significantly higher mean concentrations of histamine when treated with clemastine than with saline. The shift of the cumulative log histamine dose-reponse curve suggests that such protection is due to competitive antagonism to the inhaled clemastine. Clemastine did not protect subjects against methacholine-induced bronchoconstriction, which suggests that its bronchodilator properties are not related to any anticholinergic action.     

Propranolol inhalation challenge in relation to histamine response in children with asthma.

The relation between airway responsiveness to propranolol and histamine was studied in 32 asthmatic children. Propranolol and histamine were given by nebuliser to a maximum dose of 16 mg/ml and 32 mg/ml respectively and the response was measured as the provocative concentration of agonist causing a 20% fall in FEV1 (PC20). A PC20 histamine value of less than 32 mg/ml was obtained in 24 of the 32 children, of whom 15 had a measurable PC20 propranolol (less than 16 mg/ml). In these 24 children the geometric mean PC20 histamine was 4.5 mg/ml and 14.4 mg/ml respectively in those with and without a measurable PC20 propranolol (p = 0.023). There was a linear relationship between histamine and propranolol PC20 values (r = 0.60), and between PC20 histamine and FEV1 % predicted (r = 0.43), but not between PC20 propranolol and FEV1 % predicted (r = 0.38). In an open time course study in 12 children with asthma recovery of FEV1 after inhaled propranolol was incomplete in seven of the children after 90 minutes. When inhaled propranolol was followed by inhaled ipratropium bromide in a further 11 children FEV1 had returned to baseline in all children after 60 minutes. Thus propranolol inhalation can be used in children with asthma to assess the contribution of the beta adrenergic system to the regulation of bronchial smooth muscle tone. The test has several disadvantages in comparison with histamine provocation-long duration, the prolonged action of propranolol, and the fact that only the children with substantial hyperreactivity to histamine react to propranolol.     

Airway calibre as a confounder in interpreting bronchial responsiveness in asthma.

BACKGROUND: The relation between airway responsiveness to constrictor agents and forced expiratory volume in one second (FEV1) is important when interpreting change in airway responsiveness after an intervention. The aim of the study was to analyse the relation between FEV1 as a percentage of predicted values (% predicted) and airway responsiveness between and within asthmatic subjects. METHODS: Results of non-specific bronchial challenge tests were pooled from two randomised crossover studies comparing the effect of a non-sedative antihistamine with placebo in 35 patients with moderate asthma. The design of the two studies was similar: the provocative concentration of either histamine (first study) or methacholine (second study) resulting in a 20% decrease in ventilatory capacity (PC20) was repeated at two week intervals while patients were treated with the antihistamine or placebo. The dose of inhaled corticosteroid was gradually reduced during the study. Data were analysed with PC20 as the dependent variable in a general linear model so that the influence on PC20 of inhaled corticosteroid dose, antihistamine, and choice of bronchoconstricting agent could be separated from the influence of FEV1% predicted. RESULTS: The correlation coefficient between mean PC20 and mean prechallenge FEV1 for each patient was 0.45. In the general linear model two thirds (65%) of the variation in PC20 was due to variation between subjects. One third of the within subject variation in PC20 could be explained by variation in prechallenge FEV1% predicted (a change in FEV1 of 27% predicted was associated with one doubling or halving of PC20). Treatment with the antihistamine had no influence on PC20, except when histamine was used as the bronchoconstricting agent. The dose of inhaled corticosteroid had a small but significant effect. CONCLUSIONS: The variation in a patient's PC20 over time (several months) is related to changes in FEV1% predicted. Variation in FEV1% predicted explains less of the variation in bronchial responsiveness between subjects where a patient specific factor, which is probably related to the pathogenesis of bronchial asthma, seems to dominate.     

Effect of a platelet activating factor antagonist, WEB 2086, on allergen induced asthmatic responses.

BACKGROUND--Platelet activating factor (PAF) has been implicated in the pathogenesis of airway hyperresponsiveness in asthma. The purpose of this study was to evaluate the effects of a selective PAF antagonist (WEB 2086), given in doses known to antagonise the effects of inhaled PAF in human subjects, on allergen induced early and late asthmatic responses and on airway hyperresponsiveness. METHODS--Eight atopic, mildly asthmatic subjects were studied during a screening period and two treatment periods. During the screening period subjects inhaled an allergen to which they were known to be sensitised and the response was measured as the fall in the forced expired volume in one second (FEV1) to show the presence of early (0-1 h) and late (3-7 h) asthmatic responses. On another day the subjects inhaled allergen diluent. During the treatment periods subjects inhaled allergen after one week's pretreatment with WEB 2086 (100 mg three times a day) or placebo administered in a randomised, double blind, crossover fashion. Histamine airway responsiveness was measured 24 hours before and 24 hours after allergen and the results were expressed as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--The maximal early asthmatic response after allergen with placebo treatment was 18.4% (SE 4.4%) and with WEB 2086 18.9% (4.4%). The maximal late response with placebo treatment was 21.7% (5.3%) and with WEB 2086 21.2% (3.0%). The log difference (before and after allergen) in histamine PC20 was 0.35 (0.06) after placebo treatment and 0.30 (0.1) after WEB 2086. CONCLUSIONS--These results indicate that one week of treatment with an orally administered PAF antagonist (WEB 2086) does not attenuate allergen induced early or late responses or airway hyperresponsiveness.     

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects. METHODS: Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). RESULTS: Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively. CONCLUSIONS: The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.




     

Comparison of fluticasone propionate and beclomethasone dipropionate on direct and indirect measurements of bronchial hyperresponsiveness in patients with stable asthma.

BACKGROUND--Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores, without increased systemic activity. The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness, assessed by both a direct (histamine) and an indirect (ultrasonically nebulised distilled water (UNDW)) provocation test. METHODS--Fluticasone propionate, 750 micrograms/day, and beclomethasone dipropionate, 1500 micrograms/day, were compared in a randomised, double blind, crossover study consisting of two six week treatment periods, each preceded by a three week single blind placebo period. Twenty one non-smoking asthmatics (mean forced expiratory volume in one second (FEV1) 74.7% predicted, mean PC20histamine 0.36 mg/ml) completed the study. RESULTS--Fluticasone propionate and beclomethasone dipropionate improved FEV1, peak flow rates, asthma symptoms, and bronchial hyperresponsiveness to the same extent. Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine (mean 2.29 [95% confidence interval 1.45 to 3.13] and 1.95 [1.07 to 2.84] doubling doses, respectively) and in PD20UNDW (1.12 [0.55 to 1.70] and 1.28 [0.88 to 1.70] doubling doses, respectively). Neither treatment changed morning serum cortisol levels, but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate, indicating smaller systemic effects of fluticasone propionate. CONCLUSIONS--These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness, assessed by provocation with both histamine and UNDW, without increased systemic activity.     

Effect of antihistamines and antiallergic drugs on responses to allergen and histamine provocation tests in asthma.

The inhibition of immediate allergen or histamine induced airflow obstruction by inhaled ketotifen, clemastine, sodium cromoglycate, and placebo was studied in two groups of asthmatic subjects. Single doses of ketotifen (0.5 mg), clemastine (0.5 mg), sodium cromoglycate (20 mg), or placebo were administered by inhalation 45 minutes before bronchial provocation testing at weekly intervals, double blind and in random order. Inhalation of ketotifen and clemastine, but not sodium cromoglycate, caused an increase in the amount of histamine which had to be administered to cause a 20% fall in FEV1 from control levels (PD20-FEV1) compared with placebo. The PD20-FEV1 for allergen increased significantly after inhalation of clemastine and sodium cromoglycate. Clemastine, primarily an H1 receptor antagonist, inhibited airflow obstruction after inhalation of both histamine and allergen. Its inhibitory effect on allergen induced asthma did not differ significantly from that of sodium cromoglycate. Ketotifen, when inhaled in a single dose of 0.5 mg before bronchial provocation testing, showed potent antihistamine activity, but there was no evidence of any additional "antianaphylactic" activity.     

Circadian change in bronchial responsiveness and airflow obstruction in asthmatic children.

To throw light on the question of whether the increase in bronchial responsiveness seen during the night is due to increased airflow obstruction, nine asthmatic children with increased airflow obstruction at night (group 1) were compared with nine without (group 2). The mean fall in forced expiratory volume in one second (FEV1) between 16.00 and 04.00 hours was 21.9% in group 1 and 2.3% in group 2. Selection of patients was based on the amplitude of change in peak expiratory flow (PEF) measured every four hours for three consecutive days at home. The study was performed in hospital on four consecutive days. Medication was withheld for three days before and during the measurements at home and in hospital. On the first day in hospital (day 4) FEV1 was measured every four hours for 24 hours. On day 6 inhaled histamine provocation tests were performed at the same times as the FEV1 measurements on day 4. Both groups showed a nocturnal fall in the provocative dose of histamine causing a 20% fall in FEV1 (PC20). The mean change in histamine PC20 from 16.00 to 04.00 hours was 1.1 doubling doses of histamine in group 1 and 1.5 doubling doses in group 2. The results indicate that the increase in nocturnal bronchial responsiveness that occurs at night is not due to an increase in airflow obstruction.     

Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5'-monophosphate in non-atopic asthma.

Inhaled adenosine 5'-monophosphate (AMP) causes bronchoconstriction in atopic asthma, probably after in vivo conversion to adenosine. It has been suggested that adenosine potentiates preformed mediator release from mast cells on the mucosal surface of the airways by interacting with specific purinoceptors, without affecting the release of newly generated mediators. The airway response of nine non-atopic subjects with "intrinsic" asthma to inhaled AMP and the influence of the oral, selective H1 histamine receptor antagonist terfenadine on this response was investigated. The geometric mean provocation concentrations of histamine and AMP required to produce a 20% fall in FEV1 (PC20) were 1.82 and 13 mmol/l. In subsequent placebo controlled time course studies the FEV1 response to a single inhalation of the PC20 histamine was ablated after pretreatment with oral terfenadine 180 mg. This dose of terfenadine caused an 80% inhibition of the bronchoconstrictor response to the PC20 AMP when measured as the area under the time course-response curve and compared with the response to PC20 AMP preceded by placebo. Terfenadine 600 mg failed to increase protection against AMP further, but both doses of terfenadine delayed the time at which the mean maximum fall in FEV1 after AMP was achieved. Terfenadine 180 mg had no effect on methacholine induced bronchoconstriction in the same subjects. These data suggest that inhaled AMP may potentiate the release of preformed mediators from preactivated mast cells in the bronchial mucosa of patients with intrinsic asthma.     

Changes in bronchial responsiveness to histamine at intervals after allergen challenge.

Bronchial responsiveness to inhaled histamine was measured two, seven, and 30 hours after allergen inhalation challenge in 19 atopic subjects. The provocative histamine concentrations causing a 20% fall in FEV1 (PC20) at these three times were compared with the baseline value, with values obtained two and seven hours after diluent inhalation, and with those obtained five to seven days after allergen challenge in the 12 late responders. Seven subjects had allergen induced isolated early asthmatic responses (delta FEV1 22.6% (SD 6.6%)) with less than a 5% late fall in FEV1. There was no change in the six histamine PC20 values measured in these seven subjects; the geometric mean PC20 was 1.0-1.3 mg/ml on all six occasions. Twelve subjects had an allergen induced early asthmatic response (delta FEV1 26.3% (9.8%)) followed by a definite (greater than 15% delta FEV1, n = 7) or equivocal (5-15% delta FEV1, n = 5) late asthmatic response. The geometric mean histamine PC20 was not significantly different two hours after allergen inhalation either from baseline (0.67 v 0.78 mg/ml) or from that seen two hours after diluent (0.67 v 0.95). It was significantly reduced at seven (0.24 mg/ml) and at 30 hours (0.44 mg/ml) but had returned to baseline when repeated five to seven days later (0.74 mg/ml). In 10 subjects with a dual response who had a repeat antigen challenge the mean early and late response and delta PC20 at seven and 30 hours were similar. These data show that bronchial responsiveness to a non-allergic stimulus has not increased two hours after allergen inhalation following spontaneous recovery of the early asthmatic response but before the start of the late asthmatic response.     

Effects of inhaled histamine, methacholine and capsaicin on sputum levels of alpha 2-macroglobulin

BACKGROUND: Plasma exudation-derived proteins and peptides contribute significantly to inflammation in the airway mucosa in vivo. In the guinea pig trachea both histamine and the neurogenic stimulant capsaicin produce acute mucosal tissue distribution and luminal entry of bulk plasma, whereas cholinergic agonists fail to produce this effect. Of these agents, only histamine induces mucosal exudation of plasma in human nasal airways. The exudative effect of the above agents on human bronchi remains unknown. METHODS: The bronchial exudative responses to inhalation of histamine, methacholine, and capsaicin were examined in two groups of healthy volunteers. Sputum was induced on three occasions in each study group by inhalation of hypertonic saline (4.5%) given as an aerosol for 40 minutes using an ultrasonic nebuliser. The second and third occasions were preceded by histamine and capsaicin challenges in the first study group, and by histamine and methacholine challenges in the second study group. Histamine and methacholine were given in cumulative doses (total doses 3160 micrograms, respectively) or until a 20% reduction in forced expiratory volume in one second (FEV1) was achieved. Cumulative doses of capsaicin were inhaled until coughing prevented the subjects from drawing a full breath. Sputum levels of alpha 2-macroglobulin (729 kDa) were measured as an index of mucosal exudation of bulk plasma. RESULTS: Histamine increased mean (SE) sputum levels of alpha 2-macroglobulin from 2.72 (1.01) micrograms/ml (95% confidence interval (CI) 0.49 to 4.94) to 18.38 (8.03) micrograms/ml (95% CI 0.49 to 36.27) in the first group, and from 1.66 (0.84) micrograms/ml (95% CI -0.18 to 3.49) to 9.43 (3.63) micrograms/ml (95% CI 1.59 to 17.27) in the second group. In contrast, capsaicin evoked no exudation (sputum levels of alpha 2- macroglobulin 1.21 (0.28) micrograms/ml (95% CI 0.59 to 1.83)) and methacholine produced a minor increase in sputum levels of alpha 2- macroglobulin (2.90 (0.92) micrograms/ml (95% CI 0.90 to 4.89)). CONCLUSIONS: These results indicate that histamine is a useful agent for studying bronchial exudative responsiveness in man and that exudative effects are only of marginal importance in the cough and bronchoconstriction produced by capsaicin and methacholine.


     

Relation of the hypertonic saline responsiveness of the airways to exercise induced asthma symptom severity and to histamine or methacholine reactivity.

BACKGROUND: Conflicting views exist over whether responsiveness of the airways to hypertonic saline relates to non-specific bronchial hyperresponsiveness measured by histamine or methacholine challenge. The bronchoconstrictor responses to exercise and hypertonic saline are reported to be closely related, but the relationship between the symptoms of exercise induced asthma and airway responsiveness to hypertonic saline is not known. METHODS: In 29 asthmatic patients with a history of exercise induced asthma, the response to an ultrasonically nebulised hypertonic saline (3.6% sodium chloride) aerosol, measured as the volume of hypertonic saline laden air required to produce a fall in forced expiratory volume in one second (FEV1) of > or = 20% (PD20), was compared with the concentration of histamine (PC20; group 1) and methacholine (PC20; group 2) producing a 20% fall in baseline FEV1 and exercise induced asthma symptom severity score (groups 1 and 2). The hypertonic responsiveness was determined in a dose-response manner to a maximum dose of 310 1 and the exercise induced asthma symptom severity was scored on a scale of 0-5. RESULTS: Of the 29 patients, 23 (79%) were responsive to the hypertonic saline, with PD20 values ranging from 9 to 310 1. A significant correlation was found between the PD20 hypertonic saline and the exercise induced asthma symptom score. There was no significant correlation between the PD20 response to hypertonic saline and the histamine PC20 or methacholine PC20. The exclusion of those subjects who failed to respond to hypertonic saline improved the relationship between hypertonic saline and methacholine PC20. No significant correlation was found between the exercise induced asthma symptom score and histamine PC20 or methacholine PC20. CONCLUSION: These findings suggest that hypertonic saline responsiveness bears a closer relationship to the severity of exercise induced asthma symptoms than to the non-specific bronchial hyperresponsiveness measured by histamine or methacholine reactivity.     

Effect of acute alterations in inspired oxygen tension on methacholine induced bronchoconstriction in patients with asthma

BACKGROUND: Recent in vitro and in vivo studies in animals have suggested that ambient oxygen tension may influence airway responsiveness to bronchoconstrictor stimuli. These observations may have relevance to the management of acute exacerbations of asthma. The present studies were designed to examine the influence of inspired oxygen tension (Fio2 1.0, 0.21, 0.15) on methacholine-induced broncho- constriction in patients with asthma. METHODS: In a dual study two groups of asthmatic patients performed methacholine inhalation challenges breathing either air (Fio2 0.21) or a hypoxic gas mixture (Fio2 0.15) in study 1 and air (Fio2 0.21) or hyperoxia (Fio2 1.0) in study 2. The gases were administered through a closed breathing circuit in a randomised double blind fashion. The PC20 values (dose of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) were calculated after each methacholine challenge by linear interpolation from the logarithmic dose response curve. Plasma catecholamine levels were measured before and after methacholine challenges as well as heart rate, oxygen saturation, and percentage end tidal carbon dioxide levels. RESULTS: The geometric mean PC20 value for methacholine was significantly lower on the hypoxic study day than on the normoxic day in study 1 (mean difference in PC20 values 2.88 mg/ml (95% CI 1.4 to 5.3); p < 0.05), but there was no significant difference in the geometric mean PC20 value for methacholine between the hyperoxic and normoxic study days in study 2 (mean difference in PC20 values 1.45 mg/ ml (95% CI 0.83 to 2.51)). CONCLUSIONS: Acute hypoxia potentiates methacholine induced bronchoconstriction and acute hyperoxia has no effect in mild to moderate patients with stable asthma.