Relationship between the acid-induced cough response and airway responsiveness and obstruction in children with asthma.

BACKGROUND: In children with asthma little is known about the direct effect of the bronchoconstrictor and bronchodilator response on the cough threshold, or the relationship between bronchial responsiveness and the cough threshold. A study was undertaken to determine the effect of histamine-induced bronchoconstriction and salbutamol-induced bronchodilatation on the cough threshold in response to inhaled acetic acid, and to examine the relationship between the acetic acid cough threshold and bronchial hyperresponsiveness to histamine in children with asthma. METHODS: Nineteen children with asthma (16 boys) of mean (SE) age 10.6 (0.6) years were enrolled in the study. On day 1 each underwent a histamine inhalation challenge to determine the provocative concentration causing a fall in forced expiratory volume in one second (FEV1) of more than 20% (PC20) as an index of individual bronchial hyperresponsiveness. On day 2 the acetic acid cough threshold was determined before and just after the inhalation of the PC20 concentration of histamine, and then salbutamol (1 mg/m2) was inhaled to relieve the bronchoconstriction. Ten of the 19 patients (eight boys) of mean age 12.2 (0.7) years also tried acetic acid inhalation challenge just after salbutamol inhalation. RESULTS: There was no relationship between the bronchial responsiveness to histamine and acetic acid cough threshold in these patients. The acetic acid cough threshold after histamine inhalation was similar to that before histamine, although FEV1 decreased after histamine. In the 10 patients who also tried acetic acid inhalation challenge after salbutamol the cough threshold did not change. CONCLUSIONS: These findings suggest that acid-induced cough sensitivity and bronchomotor tone are independently regulated in children with asthma.     

Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects.

BACKGROUND--It has recently been reported that acetaldehyde induces bronchoconstriction indirectly via histamine release. However, no study has been performed to assess whether acetaldehyde worsens bronchial responsiveness in asthmatic subjects so this hypothesis was tested. METHODS--Methacholine provocation was performed on three occasions: (1) after pretreatment with oral placebo and inhaled saline (P-S day), (2) after placebo and inhaled acetaldehyde (P-A day), and (3) after a potent histamine H1 receptor antagonist terfenadine and acetaldehyde (T-A day) in a double blind, randomised, crossover fashion. Nine asthmatic subjects inhaled 0.8 mg/ml acetaldehyde or saline for four minutes. After each inhalation a methacholine provocation test was performed. RESULTS--Methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) on the P-A day (0.48 mg/ml, 95% CI 0.21 to 1.08) and T-A day (0.41 mg/ml, 95% CI 0.22 to 0.77) were lower than those on the P-S day (0.85 mg/ml, 95% CI 0.47 to 1.54). There was no change in the PC20-MCh between the P-A and T-A days. A correlation was observed between the logarithmic values of PC20-MCh (log PC20-MCh) on the P-S day and the potentiating effect of acetaldehyde on the methacholine responsiveness [(log PC20-MCh on P-A day)-(log PC20-MCh on P-S day)] (rho = 0.82). CONCLUSIONS--Acetaldehyde induces bronchial hyperresponsiveness in patients with asthma by mechanisms other than histamine release.     

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.     

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.




     

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.     

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.     

Airway anesthesia alone does not explain attenuation of histamine-induced bronchospasm by local anesthetics: a comparison of lidocaine, ropivacaine, and dyclonine

BACKGROUND: Lidocaine inhalation attenuates histamine-induced bronchospasm while evoking airway anesthesia. Because this occurs at plasma concentrations much lower than those required for intravenous lidocaine to attenuate bronchial reactivity, this effect is likely related to topical airway anesthesia and presumably independent of the specific local anesthetic used. Therefore, the authors tested the effect of dyclonine, lidocaine, and ropivacaine inhalation on histamine-induced bronchospasm in 15 volunteers with bronchial hyperreactivity. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. Histamine challenge was repeated after inhalation of dyclonine, lidocaine, ropivacaine, or placebo on 4 different days in a randomized, double-blind fashion. Lung function, bronchial hyperreactivity to histamine, duration of local anesthesia, and lidocaine and ropivacaine plasma concentrations were measured. Statistical analyses were performed with the Friedman and Wilcoxon rank tests. Data are presented as mean +/- SD. RESULTS: The inhaled histamine concentration necessary for a 20% decrease of forced expiratory volume in 1 s (PC20) was 7.0 +/- 5.0 mg/ml at the screening evaluation. Lidocaine and ropivacaine inhalation increased PC20 significantly to 16.1 +/- 12.9 and 16.5 +/- 13.6 mg/ml (P = 0.007), whereas inhalation of dyclonine and saline did not (9.1 +/- 8.4 and 6.1 +/- 5.0 mg/ml, P = 0.7268). Furthermore, in contrast to saline and lidocaine, inhalation of both ropivacaine and dyclonine significantly decreased forced expiratory volume in 1 s from baseline (P = 0.0016 and 0.0018, respectively). The longest lasting and most intense anesthesia developed after dyclonine inhalation (48 +/- 13 vs. 28 +/- 8 [lidocaine] and 25 +/- 4 min [ropivacaine]). CONCLUSION: Both lidocaine and the new amide local anesthetic ropivacaine significantly attenuate histamine-induced bronchospasm. In contrast, dyclonine, despite its longer lasting and more intense local anesthesia, does not alter histamine-evoked bronchoconstriction and irritates the airways. Thus, airway anesthesia alone does not necessarily attenuate bronchial hyperreactivity. Other properties of inhaled local anesthetics may be responsible for attenuation of bronchial hyperreactivity.     

Airway Anesthesia Alone Does Not Explain Attenuation of Histamine-induced Bronchospasm by Local Anesthetics: A Comparison of Lidocaine, Ropivacaine, and Dyclonine

Background: Lidocaine inhalation attenuates histamine-induced bronchospasm while evoking airway anesthesia. Because this occurs at plasma concentrations much lower than those required for intravenous lidocaine to attenuate bronchial reactivity, this effect is likely related to topical airway anesthesia and presumably independent of the specific local anesthetic used. Therefore, the authors tested the effect of dyclonine, lidocaine, and ropivacaine inhalation on histamine-induced bronchospasm in 15 volunteers with bronchial hyperreactivity.

Methods: Bronchial hyperreactivity was verified by an inhalational histamine challenge. Histamine challenge was repeated after inhalation of dyclonine, lidocaine, ropivacaine, or placebo on 4 different days in a randomized, double-blind fashion. Lung function, bronchial hyperreactivity to histamine, duration of local anesthesia, and lidocaine and ropivacaine plasma concentrations were measured. Statistical analyses were performed with the Friedman and Wilcoxon rank tests. Data are presented as mean +/- SD.

Results: The inhaled histamine concentration necessary for a 20% decrease of forced expiratory volume in 1 s (PC20) was 7.0 +/- 5.0 mg/ml at the screening evaluation. Lidocaine and ropivacaine inhalation increased PC20 significantly to 16.1 +/- 12.9 and 16.5 +/- 13.6 mg/ml (P = 0.007), whereas inhalation of dyclonine and saline did not (9.1 +/- 8.4 and 6.1 +/- 5.0 mg/ml, P = 0.7268). Furthermore, in contrast to saline and lidocaine, inhalation of both ropivacaine and dyclonine significantly decreased forced expiratory volume in 1 s from baseline (P = 0.0016 and 0.0018, respectively). The longest lasting and most intense anesthesia developed after dyclonine inhalation (48 +/- 13 vs. 28 +/- 8 [lidocaine] and 25 +/- 4 min [ropivacaine]).     

Lidocaine exerts its effect on induced bronchospasm by mitigating reflexes, rather than by attenuation of smooth muscle contraction

BACKGROUND: Lidocaine inhalation attenuates histamine-induced bronchoconstriction, as well as bronchoconstriction elicited by mechanical irritation. This effect could be mediated by direct effects on smooth muscle or by reflex attenuation. Therefore, we evaluated whether lidocaine attenuated the bronchial response of direct smooth muscle stimulation with methacholine. METHODS: In 15 volunteers with bronchial hyperreactivity, a methacholine challenge was performed following the inhalation of lidocaine, dyclonine (which does not attenuate bronchial reactivity) or saline on three different days in a randomized, double-blind fashion. Lung function, response to methacholine, and lidocaine and dyclonine plasma concentrations were measured. RESULTS: The inhaled methacholine concentration (PC20) necessary for a 20% decrease in the forced expiratory volume in 1 s (FEV1) was 8.8 +/- 6.1 mg/ml at the screening evaluation. The sensitivity to methacholine challenge (PC20) remained unchanged regardless of which solution was inhaled (9.1 +/- 7.5 mg/ml for lidocaine, 10.2 +/- 9.0 mg/ml for dyclonine and 9.8 +/- 8.3 mg/ml for saline; P = 0.58, means +/- standard deviation). Furthermore, the inhalation of all three solutions caused a significant decrease in FEV1 from baseline (P = 0.0007), with a significantly larger effect for dyclonine than lidocaine (P = 0.0153). CONCLUSIONS: Although both inhaled and intravenous lidocaine attenuates histamine-evoked bronchoconstriction, it does not alter the response to methacholine. Therefore, the attenuation of bronchial reactivity by lidocaine appears to be related solely to neurally mediated reflex attenuation, rather than to the attenuation of direct constriction of airway smooth muscle.     

Comparison of sulphur dioxide and metabisulphite airway reactivity in subjects with asthma.

BACKGROUND--In asthmatic subjects bronchoconstriction is induced by inhalation of the common food preservatives sulphur dioxide (SO2) and metabisulphite (MBS). SO2 and MBS challenges share many similarities, but it is not known whether they are equivalent. In this study of subjects with mild clinical asthma equivalence was assessed by comparing SO2 and MBS reactivity by estimating the total dose of SO2 inhaled during SO2 and MBS challenges, and by calculating SO2 uptake during both challenges. In addition, as the MBS solutions inhaled were acidic and hyperosmolar, the effect of these factors on MBS responsiveness was investigated. METHODS--Fifteen subjects were challenged on separate days with doubling (0.5 to 8.0 ppm) concentrations of SO2 gas inhaled during three minute periods of isocapnic hyperventilation and MBS administered in doses ranging from 0.1 to 12.8 mumol using the Wright protocol. On two other days SO2 and MBS challenges were preceded by a challenge with phosphate buffered saline (PBS) solutions of pH and osmolarity similar to MBS solutions. Response was measured as the dose or concentration causing a 20% fall in FEV1 (PD20 or PC20). RESULTS--All subjects reacted to MBS and 14 responded to SO2. Geometric mean histamine PD20 was 1.61 mumol (95% confidence interval 0.72 to 3.60). MBS and SO2 airway responsiveness were not significantly related. Estimates of the mean concentration of SO2 inhaled during SO2 and MBS challenges differed, as did estimates of the mean SO2 uptake during both challenges. MBS and SO2 reactivity were not affected by prior challenge with PBS solutions. CONCLUSIONS--SO2 and MBS challenges are not comparable. MBS reactivity was not affected by the hyperosmolar, acidic nature of its solutions.     

Effects of a thromboxane synthetase inhibitor (OKY-046) and a lipoxygenase inhibitor (AA-861) on bronchial responsiveness to acetylcholine in asthmatic subjects.

The effect of a selective thromboxane synthetase inhibitor, OKY-046, and a selective 5-lipoxygenase inhibitor, AA-861, on bronchial responsiveness to acetylcholine was studied in 23 asthmatic subjects. The provocative concentration of acetylcholine producing a 20% fall in forced expiratory volume in one second (PC20 FEV1) was measured before and after oral administration of OKY-046 (3000 mg over four days) and AA-861 (1100 mg over four days) and inhalation of OKY-046 (30 mg) in 10, 10, and nine asthmatic subjects respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by oral OKY-046, oral AA-861, or inhaled OKY-046. The geometric mean value of PC20 FEV1 increased significantly from 0.55 to 2.24 mg/ml after oral OKY-046, but was unchanged after inhalation of OKY-046 and after oral administration of AA-861. These results suggest that thromboxane A2 may play a part in bronchial hyperresponsiveness to acetylcholine.     

Combined Intravenous Lidocaine and Inhaled Salbutamol Protect against Bronchial Hyperreactivity More Effectively than Lidocaine or Salbutamol Alone

Background: Airway instrumentation in persons with asthma is linked to the risk of life-threatening bronchospasm. To attenuate the response to airway irritation, intravenous lidocaine is recommended (based on animal experiments) and mitigates the response to histamine inhalation in asthmatic volunteers. However, the effects of lidocaine have not been compared with standard prophylaxis with [Greek small letter beta]-sympathomimetic aerosols. Therefore, the effect of lidocaine, salbutamol, combined treatment, and placebo control were tested in awake volunteers with bronchial hyperreactivity.

Methods: After approval from the local ethics committee, 15 persons, who were selected because they showed a decrease in forced expiratory volume in 1 s (FEV1) more than 20% of baseline in response to inhaled histamine in a concentration less than 18 mg/ml (PC20), were enrolled in a placebo-controlled, double-blind, and randomized study. The challenge was repeated on four different days and the volunteers were pretreated with either intravenous lidocaine, inhalation of salbutamol, inhalation of salbutamol plus intravenous lidocaine, or placebo. Lidocaine plasma concentrations were also measured. Statistical analyses included the Friedman test and Wilcoxon's rank sum.

Results: The baseline PC20 was 6.4 +/- 4.3 mg/ml. Intravenous lidocaine and salbutamol aerosol both significantly increased the histamine threshold to 14.2 +/- 9.5 mg/ml and 16.8 +/- 10.9 mg/ml, respectively (mean +/- SD). However, the combination of lidocaine and salbutamol significantly increased the PC20 even further to 30.7 +/- 15.7 mg/ml than did salbutamol or lidocaine alone.     

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.     

Cigarette smoke inhalation patterns and bronchial reactivity.

The manner in which a cigarette is smoked varies considerably between individuals and may be an important determinant of the altered bronchial reactivity observed in cigarette smokers. Twenty smokers were examined to determine the relationship between cigarette smoke inhalation patterns and bronchial reactivity. Inhalation patterns were measured non-invasively with a respiratory inductive plethysmograph and these were related to the provocative concentration of histamine that caused a 20% fall in FEV1 (PC20) and to the cough threshold for inhaled citric acid. Histamine PC20 values were inversely correlated with depth and rate of inhalation. Cough threshold was inversely correlated with greater cigarette consumption and with depth of inhalation.     

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.     

Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease.

Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma. The aim of the present randomised, double blind study was to assess the effect of eight weeks' treatment with inhaled budesonide in non-allergic smokers with chronic obstructive lung disease. Twenty four subjects (23 male) entered the study. Their ages ranged from 40 to 70 (mean 57) years, with a mean of 35 (range 9-80) pack years of smoking; the mean FEV1 was 53% (range 32-74%) predicted and geometric mean PC20 (histamine concentration causing a 20% fall in FEV1) 0.96 (range 0.07-7.82) mg/ml. After a two week washout, single blind, placebo period, 12 patients were allocated to treatment with budesonide 1600 microgram/day and 12 to placebo for eight weeks. The only additional drug to be taken was ipratropium bromide "if needed." Twenty one patients completed the study, 10 in the budesonide group and 11 in the placebo group. The standard deviation of the difference between duplicate measurements of PC20 histamine and citric acid cough threshold made two weeks apart was below one doubling dose step. There was a significant reduction in dyspnoea in the budesonide group, but otherwise no change in symptom scores or use of ipratropium bromide over the eight weeks of treatment within or between the two groups. No significant differences in spirometric values, peak expiratory flow, PC20 histamine, or citric acid cough threshold were found between the groups. Although differences were not significant, some of the changes showed a trend in favour of budesonide. Whether a longer observation period would show a significant influence of inhaled corticosteroids in patients with chronic obstructive lung disease remains to be determined.     

Protective effect of drugs on histamine-induced asthma.

Controlled standardised histamine inhalation tests were carried out in 21 asthmatics to determine the degree of non-specific bronchial hyperreactivity with and without prior treatment with several anti-asthmatic drugs. A significant protective effect was produced by inhaled salbutamol, 200 microgram, ingested salbutamol, 4 mg, inhaled Sch1000, 40 microgram inhaled atropine sulphate, 290 microgram, and ingested choline theophylinate (200 or 400 mg) producing serum theophylline levels over 10 mg/l. Inhaled salbutamol was consistently the most effective and was significantly better than the other drugs. The protective effect between the other four was not significantly different. Drug side-effects occurred only with the ingested drugs. No significant protection was detected after ingested choline theophyllinate producing serum theophylline levels of less than 10 mg/l, inhaled sodium cromoglycate, 20 mg given once or six-hourly for one week, or ingested ascorbic acid, 1 gram.     

Changes in bronchial responsiveness to inhaled histamine over four years in middle aged male smokers and ex-smokers.

Bronchial hyperresponsiveness to inhaled histamine in smokers is associated with an accelerated annual decline in FEV1 and low baseline FEV1 values. The evolution of bronchial hyperresponsiveness and whether it precedes or follows the accelerated decline in FEV1 and reduction in FEV1 is unknown. Measurements of the provocative concentration of inhaled histamine required to reduce FEV1 by 20% (PC20) were repeated after a four year interval in 27 male smokers (mean age 59 years, smoking on average 27 cigarettes a day in 1986) and 16 men who were ex-smokers in 1982 and who remained non-smokers until 1986 (mean age 53 years in 1986). These men were originally recruited to a prospective study in 1974 and had their first PC20 measurement in 1982. PC20 was positively related to baseline FEV1 in both smokers and ex-smokers in both 1982 and 1986 (r ranging from 0.56 to 0.76, p less than 0.01). In smokers mean FEV1 fell from 83% to 77% predicted (p less than 0.001) and geometric mean PC20 from 7.11 to 3.27 mg/ml (p less than 0.001) between 1982 and 1986. The change in PC20 in individual smokers over the four years was related to change in FEV1 (p = 0.012). In ex-smokers mean FEV1 was 93% predicted both in 1982 and in 1986 and there was no significant difference in geometric mean PC20 between 1982 (6.68 mg/ml) and 1986 (5.98 mg/ml). Thus in smokers there was an accelerated annual decline in FEV1 and an increase in bronchial hyperresponsiveness as FEV1 fell. The ex-smokers had comparable levels of bronchial hyperresponsiveness in 1982. Mean PC20 values were unchanged in 1986 in these men, who showed a normal age related decline in FEV1. These longitudinal results emphasise the importance of baseline airway geometry in influencing bronchial hyperresponsiveness to histamine in middle aged smokers and ex-smokers.     

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.     

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.